TWI602802B - 殺蟲組成物及其相關之方法(四) - Google Patents
殺蟲組成物及其相關之方法(四) Download PDFInfo
- Publication number
- TWI602802B TWI602802B TW102146922A TW102146922A TWI602802B TW I602802 B TWI602802 B TW I602802B TW 102146922 A TW102146922 A TW 102146922A TW 102146922 A TW102146922 A TW 102146922A TW I602802 B TWI602802 B TW I602802B
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- Taiwan
- Prior art keywords
- alkyl
- group
- halo
- substituted
- alkoxy
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 78
- 239000000203 mixture Substances 0.000 title claims description 40
- 230000008569 process Effects 0.000 title description 10
- 230000000361 pesticidal effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 421
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 407
- 125000005843 halogen group Chemical group 0.000 claims description 396
- 125000003545 alkoxy group Chemical group 0.000 claims description 281
- 125000000217 alkyl group Chemical group 0.000 claims description 222
- 125000000623 heterocyclic group Chemical group 0.000 claims description 139
- 125000001424 substituent group Chemical group 0.000 claims description 132
- 229910052801 chlorine Inorganic materials 0.000 claims description 81
- -1 (C=O)OH Chemical group 0.000 claims description 78
- 229910052794 bromium Inorganic materials 0.000 claims description 77
- 229910052731 fluorine Inorganic materials 0.000 claims description 73
- 229910052740 iodine Inorganic materials 0.000 claims description 72
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 59
- 125000003107 substituted aryl group Chemical group 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims description 17
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 17
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 241000607479 Yersinia pestis Species 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000002013 molluscicidal effect Effects 0.000 claims description 2
- 230000002363 herbicidal effect Effects 0.000 claims 2
- 230000002147 killing effect Effects 0.000 claims 2
- 241000283984 Rodentia Species 0.000 claims 1
- 230000002353 algacidal effect Effects 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 claims 1
- 230000001887 anti-feedant effect Effects 0.000 claims 1
- 230000000855 fungicidal effect Effects 0.000 claims 1
- 239000004009 herbicide Substances 0.000 claims 1
- 239000002418 insect attractant Substances 0.000 claims 1
- 239000000077 insect repellent Substances 0.000 claims 1
- 230000000749 insecticidal effect Effects 0.000 claims 1
- 230000013011 mating Effects 0.000 claims 1
- 230000001069 nematicidal effect Effects 0.000 claims 1
- 231100000194 ovacidal Toxicity 0.000 claims 1
- 230000003151 ovacidal effect Effects 0.000 claims 1
- 239000005962 plant activator Substances 0.000 claims 1
- 239000005648 plant growth regulator Substances 0.000 claims 1
- 239000005871 repellent Substances 0.000 claims 1
- 230000002940 repellent Effects 0.000 claims 1
- 230000001954 sterilising effect Effects 0.000 claims 1
- 238000004659 sterilization and disinfection Methods 0.000 claims 1
- 230000003253 viricidal effect Effects 0.000 claims 1
- 238000005481 NMR spectroscopy Methods 0.000 description 355
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 317
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 246
- 239000000460 chlorine Substances 0.000 description 196
- 239000011541 reaction mixture Substances 0.000 description 195
- 235000019439 ethyl acetate Nutrition 0.000 description 159
- 239000007787 solid Substances 0.000 description 153
- 239000000243 solution Substances 0.000 description 144
- 125000004093 cyano group Chemical group *C#N 0.000 description 116
- 238000002360 preparation method Methods 0.000 description 109
- 239000011734 sodium Substances 0.000 description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 238000006243 chemical reaction Methods 0.000 description 86
- 239000007788 liquid Substances 0.000 description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 75
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 73
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 72
- 239000012267 brine Substances 0.000 description 72
- 229910004298 SiO 2 Inorganic materials 0.000 description 69
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 60
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 59
- 239000002904 solvent Substances 0.000 description 56
- 239000010410 layer Substances 0.000 description 55
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
- 238000003818 flash chromatography Methods 0.000 description 49
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 47
- 239000002585 base Substances 0.000 description 47
- 241000400611 Eucalyptus deanei Species 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 229960004365 benzoic acid Drugs 0.000 description 42
- 239000002253 acid Substances 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 239000003208 petroleum Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000005711 Benzoic acid Substances 0.000 description 35
- 235000010233 benzoic acid Nutrition 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 30
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000003880 polar aprotic solvent Substances 0.000 description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 22
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 17
- 239000012230 colorless oil Substances 0.000 description 17
- 239000003446 ligand Substances 0.000 description 17
- 239000000126 substance Substances 0.000 description 16
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 229910052786 argon Inorganic materials 0.000 description 15
- 125000004969 haloethyl group Chemical group 0.000 description 15
- 125000004970 halomethyl group Chemical group 0.000 description 15
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 15
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 229920002554 vinyl polymer Polymers 0.000 description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 13
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 10
- 239000003586 protic polar solvent Substances 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 101150003085 Pdcl gene Proteins 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 7
- 150000008064 anhydrides Chemical class 0.000 description 7
- 239000000010 aprotic solvent Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 7
- KSNKQSPJFRQSEI-UHFFFAOYSA-N 3,3,3-trifluoropropanoic acid Chemical compound OC(=O)CC(F)(F)F KSNKQSPJFRQSEI-UHFFFAOYSA-N 0.000 description 6
- MTTVIHLACZDSSK-UHFFFAOYSA-N 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene Chemical compound FC(F)(F)C(Br)C1=CC(Cl)=C(Cl)C(Cl)=C1 MTTVIHLACZDSSK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 125000005059 halophenyl group Chemical group 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- KOZCZZVUFDCZGG-UHFFFAOYSA-N vinyl benzoate Chemical compound C=COC(=O)C1=CC=CC=C1 KOZCZZVUFDCZGG-UHFFFAOYSA-N 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 229940050390 benzoate Drugs 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- CAAOFOPLNYBDTH-UHFFFAOYSA-N ethyl 4-ethenyl-2-methylbenzoate Chemical compound CCOC(=O)C1=CC=C(C=C)C=C1C CAAOFOPLNYBDTH-UHFFFAOYSA-N 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000002917 insecticide Substances 0.000 description 5
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 5
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 5
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- WGCJPCOBAJCKHX-UHFFFAOYSA-N 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene Chemical compound FC(F)(F)C(Br)C1=CC(Cl)=CC(Cl)=C1 WGCJPCOBAJCKHX-UHFFFAOYSA-N 0.000 description 4
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
- JDRRBNIPFNDHED-RQOWECAXSA-N 2-bromo-4-[(z)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl]benzoic acid Chemical compound C1=C(Br)C(C(=O)O)=CC=C1\C=C/C(C(F)(F)F)C1=CC(Cl)=C(Cl)C(Cl)=C1 JDRRBNIPFNDHED-RQOWECAXSA-N 0.000 description 4
- DBADNOKYDIDZBM-UHFFFAOYSA-N 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene Chemical compound FC1=C(Cl)C=C(C(Br)C(F)(F)F)C=C1Cl DBADNOKYDIDZBM-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 4
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
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- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- YISOXLVRWFDIKD-UHFFFAOYSA-N bismuth;borate Chemical compound [Bi+3].[O-]B([O-])[O-] YISOXLVRWFDIKD-UHFFFAOYSA-N 0.000 description 1
- AUEMEEMVNBYZLM-UHFFFAOYSA-N bromine;toluene Chemical compound [Br].CC1=CC=CC=C1 AUEMEEMVNBYZLM-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- SMLBZDFUAFPSMA-UHFFFAOYSA-N butyl 4-bromo-2-chlorobenzoate Chemical compound CCCCOC(=O)C1=CC=C(Br)C=C1Cl SMLBZDFUAFPSMA-UHFFFAOYSA-N 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- GOMCKELMLXHYHH-UHFFFAOYSA-L dipotassium;phthalate Chemical compound [K+].[K+].[O-]C(=O)C1=CC=CC=C1C([O-])=O GOMCKELMLXHYHH-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- QUGJYNGNUBHTNS-UHFFFAOYSA-N ethyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OCC)C1=CC=CC=C1 QUGJYNGNUBHTNS-UHFFFAOYSA-N 0.000 description 1
- RVMZEDHYPRSYOZ-UHFFFAOYSA-N ethyl 2-methyl-4-methylsulfanylbenzoate Chemical compound CCOC(=O)C1=CC=C(SC)C=C1C RVMZEDHYPRSYOZ-UHFFFAOYSA-N 0.000 description 1
- CAIKKJIIZHDMSX-UHFFFAOYSA-N ethyl 2-sulfanylbenzoate Chemical compound CCOC(=O)C1=CC=CC=C1S CAIKKJIIZHDMSX-UHFFFAOYSA-N 0.000 description 1
- WAMFVIPTXLDKMZ-UHFFFAOYSA-N ethyl 4-ethenyl-2-methylsulfanylbenzoate Chemical compound CCOC(=O)C1=CC=C(C=C)C=C1SC WAMFVIPTXLDKMZ-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 229940056881 imidacloprid Drugs 0.000 description 1
- YWTYJOPNNQFBPC-UHFFFAOYSA-N imidacloprid Chemical compound [O-][N+](=O)\N=C1/NCCN1CC1=CC=C(Cl)N=C1 YWTYJOPNNQFBPC-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000003750 molluscacide Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- XHLDCMPNOQBZQH-UHFFFAOYSA-N n-ethenylbenzamide Chemical compound C=CNC(=O)C1=CC=CC=C1 XHLDCMPNOQBZQH-UHFFFAOYSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000005645 nematicide Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000012026 peptide coupling reagents Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- USRYWZFLGFQQEB-UHFFFAOYSA-N pyrimidin-5-ylmethanamine Chemical compound NCC1=CN=CN=C1 USRYWZFLGFQQEB-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- VIHDTGHDWPVSMM-UHFFFAOYSA-N ruthenium;triphenylphosphane Chemical compound [Ru].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VIHDTGHDWPVSMM-UHFFFAOYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LCZVKKUAUWQDPX-UHFFFAOYSA-N tert-butyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl]amino]acetate Chemical compound CC(=O)OC1=CC=CC=C1CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1=CC=CC=C1OC(C)=O LCZVKKUAUWQDPX-UHFFFAOYSA-N 0.000 description 1
- ZWQXDRJLUKYHII-UHFFFAOYSA-N tert-butyl 3-ethenylindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=C(C=C)C2=C1 ZWQXDRJLUKYHII-UHFFFAOYSA-N 0.000 description 1
- IHLZXPVSSFCZLU-UHFFFAOYSA-N tert-butyl 4-bromo-2-chlorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(Br)C=C1Cl IHLZXPVSSFCZLU-UHFFFAOYSA-N 0.000 description 1
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
-
- 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
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/02—Amines; Quaternary ammonium compounds
- A01N33/04—Nitrogen directly attached to aliphatic or cycloaliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/10—Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
- A01N37/28—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof containing the group; Thio analogues thereof
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- A—HUMAN NECESSITIES
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Description
本申請案主張2012年12月19日申請之美國臨時專利申請案第61/739,025號之權益,其揭示內容明確地以引用的方式併入本文中。
本文件中揭示之發明係關於以下領域:製造適用作殺蟲劑(例如殺蟎劑、殺昆蟲劑、殺軟體動物劑及殺線蟲劑)之分子的方法、該等分子及使用該等分子控制害蟲之方法。
害蟲每年會造成全世界數百萬人死亡。另外,有超過萬種引起農業損失之害蟲物種。每年全世界農業損失總計數十億美元。
白蟻會引起各種私人及公共結構之破壞。每年全世界白蟻破壞損失總計數十億美元。
貯存食物之害蟲吃掉貯存食物並摻雜至貯存食物中。每年全世界貯存食物損失總計數十億美元,但更重
要的是,此會剝奪人們所需食物。
急需新的殺蟲劑。某些害蟲正對目前使用之殺蟲劑發展出抗性。數百種害蟲物種抗一或多種殺蟲劑。對一些較老的殺蟲劑(諸如DDT、胺基甲酸酯及有機磷酸酯)發展出抗性為熟知的。但甚至對一些較新的殺蟲劑(例如益達胺(imidacloprid))已發展出抗性。
因此,出於包括上述原因之多種原因,需要新的殺蟲劑。
在定義中給出之實例通常為非窮舉性的且不能被解釋為對本文件中揭示之發明進行限制。應理解,取代基應符合與和其連接之特定分子相關之化學鍵結規則及空間相容性限制。
「烯基」意謂由碳及氫組成之非環狀的不飽和的(至少一個碳-碳雙鍵)分支鏈或非分支鏈之取代基,例如乙烯基、烯丙基、丁烯基、戊烯基及己烯基。
「烯氧基」意謂進一步由碳-氧單鍵組成之烯基,例如烯丙氧基、丁烯氧基、戊烯氧基、己烯氧基。
「烷氧基」意謂進一步由碳-氧單鍵組成之烷基,例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基及第三丁氧基。
「烷基」意謂由碳及氫組成之非環狀的飽和的分支鏈或非分支鏈之取代基,例如甲基、乙基、(C3)烷基(其表示正丙基及異丙基);(C4)烷基(其表示正丁基、第二丁
基、異丁基及第三丁基)。
「炔基」意謂由碳及氫組成之非環狀的不飽和的(至少一個碳-碳參鍵)分支鏈或非分支鏈之取代基,例如乙炔基、炔丙基、丁炔基及戊炔基。
「炔氧基」意謂進一步由碳-氧單鍵組成之炔基,例如戊炔氧基、己炔氧基、庚炔氧基及辛炔氧基。
「芳基」意謂由氫及碳組成之環狀的芳族取代基,例如苯基、萘基及聯苯基。
「(C x -C y )」(其中下標「x」及「y」為整數,諸如1、2或3)意謂取代基之碳原子範圍,舉例而言,(C1-C4)烷基各自個別地意謂甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基及第三丁基。
「環烯基」意謂由碳及氫組成之單環或多環的不飽和的(至少一個碳-碳雙鍵)取代基,例如環丁烯基、環戊烯基、環己烯基、降烯基、雙環[2.2.2]辛烯基、四氫萘基、六氫萘基及八氫萘基。
「環烯氧基」意謂進一步由碳-氧單鍵組成之環烯基,例如環丁烯氧基、環戊烯氧基、降烯氧基及雙環[2.2.2]辛烯氧基。
「環烷基」意謂由碳及氫組成之單環或多環的飽和取代基,例如環丙基、環丁基、環戊基、降基、雙環[2.2.2]辛基及十氫萘基。
「環烷氧基」意謂進一步由碳-氧單鍵組成之環烷基,例如環丙氧基、環丁氧基、環戊氧基、降氧基及
雙環[2.2.2]辛氧基。
「鹵基」意謂氟、氯、溴及碘。
「鹵烷氧基」意謂進一步由一個至最大可能數目之相同或不同的鹵基組成之烷氧基,例如氟甲氧基、三氟甲氧基、2,2-二氟丙氧基、氯甲氧基、三氯甲氧基、1,1,2,2-四氟乙氧基及五氟乙氧基。
「鹵烷基」意謂進一步由一個至最大可能數目之相同或不同的鹵基組成之烷基,例如氟甲基、三氟甲基、2,2-二氟丙基、氯甲基、三氯甲基及1,1,2,2-四氟乙基。
「雜環基」意謂環狀取代基,其可為完全飽和、部分不飽和或完全不飽和的,其中該環狀結構含有至少一個碳及至少一個雜原子,其中該雜原子為氮、硫或氧。就硫而言,該原子可處於其他氧化態,諸如亞碸及碸。芳族雜環基之實例包括(但不限於)苯并呋喃基、苯并異噻唑基、苯并異噁唑基、苯并噁唑基、苯并噻吩基、苯并噻唑基、啉基、呋喃基、咪唑基、吲唑基、吲哚基、異吲哚基、異喹啉基、異噻唑基、異噁唑基、噁二唑基、噁唑啉基、噁唑基、酞嗪基、吡嗪基、吡唑啉基、吡唑基、噠嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喏啉基、四唑基、噻唑啉基、噻唑基、噻吩基、三嗪基及三唑基。完全飽和的雜環基之實例包括(但不限於)哌嗪基、哌啶基、嗎啉基、吡咯啶基、氧雜環丁烷基、四氫呋喃基、四氫噻吩基及四氫哌喃基。部分不飽和的雜環基之實例包括(但不限於)1,2,3,4-四氫喹啉基、4,5-二氫-噁唑基、4,5-二氫-1H-
吡唑基、4,5-二氫-異噁唑基及2,3-二氫-[1,3,4]-噁二唑基。
其他實例包括以下各者:
依據本發明之一實施例,係特地提出一種組成物,其包含根據式I之分子:
其中:(a)R1係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基
(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(b)R2係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(c)R3係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、
N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(d)R4係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(e)R5係選自
(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(f)R6為(C1-C8)鹵烷基;(g)R7係選自H、F、Cl、Br、I、OH、(C1-C8)烷氧基及鹵基(C1-C8)烷氧基;(h)R8係選自H、(C1-C8)烷基、鹵基(C1-C8)烷基、OR14及N(R14)(R15);(i)R9係選自H、F、Cl、Br、I、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、OR14及N(R14)(R15);(j)R10係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、環(C3-C6)
烷基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、NR14R15、C(=O)H、C(=O)N(R14)(R15)、CN(R14)(R15)(=NOH)、(C=O)O(C1-C8)烷基、(C=O)OH、雜環基、(C2-C8)烯基、鹵基(C2-C8)烯基、(C2-C8)炔基,(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自以下之取代基:OH、(C1-C8)烷氧基、S(C1-C8)烷基、S(O)(C1-C8)烷基、S(O)2(C1-C8)烷基、NR14R15,及(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自以下之取代基:(C1-C8)烷氧基、S(C1-C8)烷基、S(O)(C1-C8)烷基、S(O)2(C1-C8)烷基及N(R14)(R15);(k)R11係選自C(=X5)N(R14)((C1-C8)烷基C(=X5)N(R14)(R15)),其中各X5係獨立地選自O或S;(l)R12係選自(v)、H、F、Cl、Br、I、CN、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基及環(C3-C6)烷基;(m)R13係選自(v)、H、F、Cl、Br、I、CN、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基及鹵基(C1-C8)烷氧基;(n)各R14係獨立地選自H、(C1-C8)烷基、(C2-C8)烯基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、(C1-C8)烷氧基、環(C3-C6)烷基、芳基、經取
代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、N(R16)(R17)、(C1-C8)烷基-C(=O)N(R16)(R17)、C(=O)(C1-C8)烷基、C(=O)(鹵基(C1-C8)烷基)、C(=O)(C3-C6)環烷基、(C1-C8)烷基-C(=O)O(C1-C8)烷基、C(=O)H
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、(C3-C6)環烷基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)、雜環基、C(=O)(C1-C8)烷基、C(=O)O(C1-C8)烷基及側氧基,(其中該烷基、烷氧基及雜環基可進一步經F、Cl、Br、I、CN及NO2中之一或多者取代);
(o)各R15係獨立地選自H、(C1-C8)烷基、(C2-C8)烯基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、(C1-C8)烷氧基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、N(R16)(R17)、(C1-C8)烷基-C(=O)N(R16)(R17)、C(=O)(C1-C8)烷基、C(=O)(鹵基(C1-C8)烷基)、C(=O)(C3-C6)環烷基、(C1-C8)烷基-C(=O)O(C1-C8)烷基、C(=O)H
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、(C3-C6)環烷基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中
各(C1-C8)烷基經獨立地選擇)、雜環基、C(=O)(C1-C8)烷基、C(=O)O(C1-C8)烷基及側氧基,(其中該烷基、烷氧基及雜環基可進一步經F、Cl、Br、I、CN及NO2中之一或多者取代);(p)各R16係獨立地選自H、(C1-C8)烷基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經
獨立地選擇)及側氧基;(q)各R17係獨立地選自H、(C1-C8)烷基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基;(r)X1係選自N及CR12;
(s)X2係選自N、CR9及CR13;(t)X3係選自N及CR9;且(v)R12及R13共同形成含有3至4個選自C、N、O及S之原子之鍵聯,其中該鍵聯連接回至環以形成5至6員飽和或不飽和環,其中該鍵聯具有至少一個取代基X4,其中X4係選自R14、N(R14)(R15)、N(R14)(C(=O)R14)、N(R14)(C(=S)R14)、N(R14)(C(=O)N(R14)(R14))、N(R14)(C(=S)N(R14)(R14))、N(R14)(C(=O)N(R14)((C2-C8)烯基))、N(R14)(C(=S)N(R14)((C2-C8)烯基)),其中各R14經獨立地選擇。
此文件揭示具有下式(「式I」)之分子:
其中:(a)R1係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)
烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(b)R2係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵
基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(c)R3係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(d)R4係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基
(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(e)R5係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、N(R14)(R15),(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,(4)經取代之(C 1 -C 8 )烷氧基,其中該經取代之(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基,及(5)經取代之鹵基(C 1 -C 8 )烷氧基,其中該經取代之鹵基(C1-C8)烷氧基具有一或多個選自CN及NO2之取代基;(f)R6為(C1-C8)鹵烷基;(g)R7係選自H、F、Cl、Br、I、OH、(C1-C8)烷氧基及鹵基(C1-C8)烷氧基;(h)R8係選自H、(C1-C8)烷基、鹵基(C1-C8)烷基、OR14及N(R14)(R15);
(i)R9係選自H、F、Cl、Br、I、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、OR14及N(R14)(R15);(j)R10係選自(1)H、F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、環(C3-C6)烷基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、S(O)(C1-C8)烷基、S(O)(鹵基(C1-C8)烷基)、S(O)2(C1-C8)烷基、S(O)2(鹵基(C1-C8)烷基)、NR14R15、C(=O)H、C(=O)N(R14)(R15)、CN(R14)(R15)(=NOH)、(C=O)O(C1-C8)烷基、(C=O)OH、雜環基、(C2-C8)烯基、鹵基(C2-C8)烯基、(C2-C8)炔基,(2)經取代之(C 1 -C 8 )烷基,其中該經取代之(C1-C8)烷基具有一或多個選自以下之取代基:OH、(C1-C8)烷氧基、S(C1-C8)烷基、S(O)(C1-C8)烷基、S(O)2(C1-C8)烷基、NR14R15,及(3)經取代之鹵基(C 1 -C 8 )烷基,其中該經取代之鹵基(C1-C8)烷基具有一或多個選自以下之取代基:(C1-C8)烷氧基、S(C1-C8)烷基、S(O)(C1-C8)烷基、S(O)2(C1-C8)烷基及N(R14)(R15);(k)R11係選自C(=X5)N(R14)((C1-C8)烷基C(=X5)N(R14)(R15)),其中各X5係獨立地選自O或S;(l)R12係選自(v)、H、F、Cl、Br、I、CN、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基及環(C3-C6)烷基;
(m)R13係選自(v)、H、F、Cl、Br、I、CN、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基及鹵基(C1-C8)烷氧基;(n)各R14係獨立地選自H、(C1-C8)烷基、(C2-C8)烯基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、(C1-C8)烷氧基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、N(R16)(R17)、(C1-C8)烷基-C(=O)N(R16)(R17)、C(=O)(C1-C8)烷基、C(=O)(鹵基(C1-C8)烷基)、C(=O)(C3-C6)環烷基、(C1-C8)烷基-C(=O)O(C1-C8)烷基、C(=O)H
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取
代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、(C3-C6)環烷基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)、雜環基、C(=O)(C1-C8)烷基、C(=O)O(C1-C8)烷基及側氧基,(其中該烷基、烷氧基及雜環基可進一步經F、Cl、Br、I、CN及NO2中之一或多者取代);(o)各R15係獨立地選自H、(C1-C8)烷基、(C2-C8)烯基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、(C1-C8)烷氧基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、N(R16)(R17)、(C1-C8)烷基-C(=O)N(R16)(R17)、C(=O)(C1-C8)烷基、C(=O)(鹵基(C1-C8)烷基)、C(=O)(C3-C6)環烷基、(C1-C8)烷基-C(=O)O(C1-C8)烷基、C(=O)H
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、
S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、(C3-C6)環烷基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)、雜環基、C(=O)(C1-C8)烷基、C(=O)O(C1-C8)烷基及側氧基,(其中該烷基、烷氧基及雜環基可進一步經F、Cl、Br、I、CN及NO2中之一或多者取代);(p)各R16係獨立地選自H、(C1-C8)烷基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、
S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基;(q)各R17係獨立地選自H、(C1-C8)烷基、經取代之(C1-C8)烷基、鹵基(C1-C8)烷基、經取代之鹵基(C1-C8)烷基、環(C3-C6)烷基、芳基、經取代之芳基、(C1-C8)烷基-芳基、(C1-C8)烷基-(經取代之芳基)、O-(C1-C8)烷基-芳基、O-(C1-C8)烷基-(經取代之芳基)、雜環基、經取代之雜環基、(C1-C8)烷基-雜環基、(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基-雜環基、O-(C1-C8)烷基-(經取代之雜環基)、O-(C1-C8)烷基
其中各該經取代之(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之鹵基(C1-C8)烷基具有一或多個選自CN及NO2之取代基,其中各該經取代之芳基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基,且
其中各該經取代之雜環基具有一或多個選自以下之取代基:F、Cl、Br、I、CN、NO2、(C1-C8)烷基、鹵基(C1-C8)烷基、(C1-C8)烷氧基、鹵基(C1-C8)烷氧基、S(C1-C8)烷基、S(鹵基(C1-C8)烷基)、N((C1-C8)烷基)2(其中各(C1-C8)烷基經獨立地選擇)及側氧基;(r)X1係選自N及CR12;(s)X2係選自N、CR9及CR13;(t)X3係選自N及CR9;且(v)R12及R13共同形成含有3至4個選自C、N、O及S之原子之鍵聯,其中該鍵聯連接回至環以形成5至6員飽和或不飽和環(cyclic ring),其中該鍵聯具有至少一個取代基X4,其中X4係選自R14、N(R14)(R15)、N(R14)(C(=O)R14)、N(R14)(C(=S)R14)、N(R14)(C(=O)N(R14)(R14))、N(R14)(C(=S)N(R14)(R14))、N(R14)(C(=O)N(R14)((C2-C8)烯基))、N(R14)(C(=S)N(R14)((C2-C8)烯基)),其中各R14經獨立地選擇。
在本發明之另一實施例中,R1可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、CN、NO2、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、
鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R2可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、CN、NO2、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R3可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、CN、NO2、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R4可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、CN、NO2、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、
甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R5可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、CN、NO2、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R2及R4係選自F、Cl、Br、I、CN及NO2,且R1、R3及R5為H。
在本發明之另一實施例中,R2、R3及R4係選自F、Cl、Br、I、CN及NO2,且R1及R5為H。
在本發明之另一實施例中,R2、R3及R4係獨立地選自F及Cl,且R1及R5為H。
在本發明之另一實施例中,R1係選自Cl及H。
在本發明之另一實施例中,R2係選自CF3、CH3、Cl、F及H。
在本發明之另一實施例中,R3係選自OCH3、CH3、F、Cl或H。
在本發明之另一實施例中,R4係選自CF3、CH3、Cl、F及H。
在本發明之另一實施例中,R5係選自F、Cl及H。
在本發明之另一實施例中,R6可選自以下中之一或多者之任何組合:鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基及鹵基(C8)烷基。
在本發明之另一實施例中,R6為三氟甲基。
在本發明之另一實施例中,R7可選自以下中之一或多者之任何組合:H、F、Cl、Br及I。
在本發明之另一實施例中,R7係選自H、OCH3及OH。
在本發明之另一實施例中,R8可選自以下中之一或多者之任何組合:H、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基及鹵基(C8)烷基。
在本發明之另一實施例中,R8係選自CH3及H。
在本發明之另一實施例中,R9可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)
烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R10可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、CN、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲氧基、乙氧基、(C3)烷氧基、(C4)烷氧基、(C5)烷氧基、(C6)烷氧基、(C7)烷氧基、(C8)烷氧基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基、鹵基(C8)烷氧基、環丙基、環丁基、環戊基及環己基。
在本發明之另一實施例中,R10可選自以下中之一或多者之任何組合:H、Cl、Br、CH3及CF3。
在本發明之另一實施例中,R10係選自Br、C(=NOH)NH2、C(=O)H、C(=O)NH2、C(=O)OCH2CH3、C(=O)OH、CF3、CH2CH3、CH2OH、CH3、Cl、CN、F、H、NH2、NHC(=O)H、NHCH3、NO2、OCH3、OCHF2及吡啶基。
在本發明之另一實施例中,R11可選自以下中之一或多者之任何組合:C(=O)N(H)(C((CH3)2)C(=O)N(H)(CH2CF3))、C(=O)N(H)(CH(CH3)C(=O)N(H)(CH2CF3))、C(=O)N(H)(CH(CH2CH3)C(=O)N(H)(CH2CF3))、C(=O)N(H)(CH(CH3)C(=S)N(H)
(CH2CF3))、C(=O)N(H)(C((CH3)2)C(=S)N(H)(CH2CF3))及C(=S)N(H)(C((CH3)2)C(=S)N(H)(CH2CF3))。
在本發明之另一實施例中,R11為C(=(O或S))N(H)(((C1-C8)烷基)C(=(O或S))N(H)(鹵基(C1-C8)烷基)),其可與R1至R10及X1至X3之任何實施例組合使用。
在本發明之另一實施例中,R12可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R12係選自CH3及H。
在本發明之另一實施例中,R13可選自以下中之一或多者之任何組合:H、F、Cl、Br、I、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、鹵甲氧基、鹵乙氧基、鹵基(C3)烷氧基、鹵基(C4)烷氧基、鹵基(C5)烷氧基、鹵基(C6)烷氧基、鹵基(C7)烷氧基及鹵基(C8)烷氧基。
在本發明之另一實施例中,R13係選自CH3、Cl及H。
在本發明之另一實施例中,R12-R13為含有CH=CHCH=CH之烴基鍵聯。
在本發明之另一實施例中,R14可選自以下中之一或多者之任何組合:H、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲基-芳基、乙基-芳基、(C3)烷基-芳基、(C4)烷基-芳基、(C5)烷基-芳基、(C6)烷基-芳基、(C7)烷基-芳基、(C8)烷基-芳基、甲基-(經取代之芳基)、乙基-(經取代之芳基)、(C3)烷基-(經取代之芳基)、(C4)烷基-(經取代之芳基)、(C5)烷基-(經取代之芳基)、(C6)烷基-(經取代之芳基)、(C7)烷基-(經取代之芳基)、(C8)烷基-(經取代之芳基)、O-甲基-芳基、O-乙基-芳基、O-(C3)烷基-芳基、O-(C4)烷基-芳基、O-(C5)烷基-芳基、O-(C6)烷基-芳基、O-(C7)烷基-芳基、O-(C8)烷基-芳基、O-甲基-(經取代之芳基)、O-乙基-(經取代之芳基)、O-(C3)烷基-(經取代之芳基)、O-(C4)烷基-(經取代之芳基)、O-(C5)烷基-(經取代之芳基)、O-(C6)烷基-(經取代之芳基)、O-(C7)烷基-(經取代之芳基)、O-(C8)烷基-(經取代之芳基)、甲基-雜環基、乙基-雜環基、(C3)烷基-雜環基、(C4)烷基-雜環基、(C5)烷基-雜環基、(C6)烷基-雜環基、(C7)烷基-雜環基、(C8)烷基-雜環基、甲基-(經取代之雜環基)、乙基-(經取代之雜環基)、(C3)烷基-(經取代之雜環基)、(C4)烷基-(經取代之雜環基)、(C5)烷基-(經取代之雜環基)、(C6)烷基-(經取代之雜環基)、
(C7)烷基-(經取代之雜環基)、(C8)烷基-(經取代之雜環基)、O-甲基-雜環基、O-乙基-雜環基、O-(C3)烷基-雜環基、O-(C4)烷基-雜環基、O-(C5)烷基-雜環基、O-(C6)烷基-雜環基、O-(C7)烷基-雜環基、O-(C8)烷基-雜環基、O-甲基-(經取代之雜環基)、O-乙基-(經取代之雜環基)、O-(C3)烷基-(經取代之雜環基)、O-(C4)烷基-(經取代之雜環基)、O-(C5)烷基-(經取代之雜環基)、O-(C6)烷基-(經取代之雜環基)、O-(C7)烷基-(經取代之雜環基)、O-(C8)烷基-(經取代之雜環基)、甲基-C(=O)N(R16)(R17)、乙基-C(=O)N(R16)(R17)、(C3)烷基-C(=O)N(R16)(R17)、(C4)烷基-C(=O)N(R16)(R17)、(C5)烷基-C(=O)N(R16)(R17)、(C6)烷基-C(=O)N(R16)(R17)、(C7)烷基-C(=O)N(R16)(R17)及(C8)烷基-C(=O)N(R16)(R17)。
在本發明之另一實施例中,R14可選自以下中之一或多者之任何組合:H、CH3、CH2CF3、CH2-鹵吡啶基、側氧基-吡咯啶基、鹵苯基、硫雜環丁烷基、CH2-苯基、CH2-吡啶基、硫雜環丁烷基-二氧化物、CH2-鹵噻唑基、C((CH3)2)-吡啶基、N(H)(鹵苯基)、CH2-嘧啶基、CH2-四氫呋喃基、CH2-呋喃基、O-CH2-鹵吡啶基及CH2C(=O)N(H)(CH2CF3)。
在本發明之另一實施例中,R15可選自以下中之一或多者之任何組合:H、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲基-芳基、乙基
-芳基、(C3)烷基-芳基、(C4)烷基-芳基、(C5)烷基-芳基、(C6)烷基-芳基、(C7)烷基-芳基、(C8)烷基-芳基、甲基-(經取代之芳基)、乙基-(經取代之芳基)、(C3)烷基-(經取代之芳基)、(C4)烷基-(經取代之芳基)、(C5)烷基-(經取代之芳基)、(C6)烷基-(經取代之芳基)、(C7)烷基-(經取代之芳基)、(C8)烷基-(經取代之芳基)、O-甲基-芳基、O-乙基-芳基、O-(C3)烷基-芳基、O-(C4)烷基-芳基、O-(C5)烷基-芳基、O-(C6)烷基-芳基、O-(C7)烷基-芳基、O-(C8)烷基-芳基、O-甲基-(經取代之芳基)、O-乙基-(經取代之芳基)、O-(C3)烷基-(經取代之芳基)、O-(C4)烷基-(經取代之芳基)、O-(C5)烷基-(經取代之芳基)、O-(C6)烷基-(經取代之芳基)、O-(C7)烷基-(經取代之芳基)、O-(C8)烷基-(經取代之芳基)、甲基-雜環基、乙基-雜環基、(C3)烷基-雜環基、(C4)烷基-雜環基、(C5)烷基-雜環基、(C6)烷基-雜環基、(C7)烷基-雜環基、(C8)烷基-雜環基、甲基-(經取代之雜環基)、乙基-(經取代之雜環基)、(C3)烷基-(經取代之雜環基)、(C4)烷基-(經取代之雜環基)、(C5)烷基-(經取代之雜環基)、(C6)烷基-(經取代之雜環基)、(C7)烷基-(經取代之雜環基)、(C8)烷基-(經取代之雜環基)、O-甲基-雜環基、O-乙基-雜環基、O-(C3)烷基-雜環基、O-(C4)烷基-雜環基、O-(C5)烷基-雜環基、O-(C6)烷基-雜環基、O-(C7)烷基-雜環基、O-(C8)烷基-雜環基、O-甲基-(經取代之雜環基)、O-乙基-(經取代之雜環基)、O-(C3)烷基-(經取代之雜環基)、O-(C4)烷基-(經取代之雜環基)、O-(C5)烷基-(經取代之雜環基)、O-(C6)烷基-(經取代之雜環基)、O-(C7)
烷基-(經取代之雜環基)、O-(C8)烷基-(經取代之雜環基)、甲基-C(=O)N(R16)(R17)、乙基-C(=O)N(R16)(R17)、(C3)烷基-C(=O)N(R16)(R17)、(C4)烷基-C(=O)N(R16)(R17)、(C5)烷基-C(=O)N(R16)(R17)、(C6)烷基-C(=O)N(R16)(R17)、(C7)烷基-C(=O)N(R16)(R17)及(C8)烷基-C(=O)N(R16)(R17)。
在本發明之另一實施例中,R15可選自以下中之一或多者之任何組合:H、CH3、CH2CF3、CH2-鹵吡啶基、側氧基-吡咯啶基、鹵苯基、硫雜環丁烷基、CH2-苯基、CH2-吡啶基、硫雜環丁烷基-二氧化物、CH2-鹵噻唑基、C((CH3)2)-吡啶基、N(H)(鹵苯基)、CH2-嘧啶基、CH2-四氫呋喃基、CH2-呋喃基、O-CH2-鹵吡啶基及CH2C(=O)N(H)(CH2CF3)。
在本發明之另一實施例中,R16可選自以下中之一或多者之任何組合:H、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲基-芳基、乙基-芳基、(C3)烷基-芳基、(C4)烷基-芳基、(C5)烷基-芳基、(C6)烷基-芳基、(C7)烷基-芳基、(C8)烷基-芳基、甲基-(經取代之芳基)、乙基-(經取代之芳基)、(C3)烷基-(經取代之芳基)、(C4)烷基-(經取代之芳基)、(C5)烷基-(經取代之芳基)、(C6)烷基-(經取代之芳基)、(C7)烷基-(經取代之芳基)、(C8)烷基-(經取代之芳基)、O-甲基-芳基、O-乙基-芳基、O-(C3)烷基-芳基、O-(C4)烷基-芳基、O-(C5)烷基-芳基、O-(C6)烷基-
芳基、O-(C7)烷基-芳基、O-(C8)烷基-芳基、O-甲基-(經取代之芳基)、O-乙基-(經取代之芳基)、O-(C3)烷基-(經取代之芳基)、O-(C4)烷基-(經取代之芳基)、O-(C5)烷基-(經取代之芳基)、O-(C6)烷基-(經取代之芳基)、O-(C7)烷基-(經取代之芳基)、O-(C8)烷基-(經取代之芳基)、甲基-雜環基、乙基-雜環基、(C3)烷基-雜環基、(C4)烷基-雜環基、(C5)烷基-雜環基、(C6)烷基-雜環基、(C7)烷基-雜環基、(C8)烷基-雜環基、甲基-(經取代之雜環基)、乙基-(經取代之雜環基)、(C3)烷基-(經取代之雜環基)、(C4)烷基-(經取代之雜環基)、(C5)烷基-(經取代之雜環基)、(C6)烷基-(經取代之雜環基)、(C7)烷基-(經取代之雜環基)、(C8)烷基-(經取代之雜環基)、O-甲基-雜環基、O-乙基-雜環基、O-(C3)烷基-雜環基、O-(C4)烷基-雜環基、O-(C5)烷基-雜環基、O-(C6)烷基-雜環基、O-(C7)烷基-雜環基、O-(C8)烷基-雜環基、O-甲基-(經取代之雜環基)、O-乙基-(經取代之雜環基)、O-(C3)烷基-(經取代之雜環基)、O-(C4)烷基-(經取代之雜環基)、O-(C5)烷基-(經取代之雜環基)、O-(C6)烷基-(經取代之雜環基)、O-(C7)烷基-(經取代之雜環基)及O-(C8)烷基-(經取代之雜環基)。
在本發明之另一實施例中,R16可選自以下中之一或多者之任何組合:H、CH2CF3、環丙基、硫雜環丁烷基、硫雜環丁烷基二氧化物及鹵苯基。
在本發明之另一實施例中,R17可選自以下中之一或多者之任何組合:H、甲基、乙基、(C3)烷基、(C4)烷基、(C5)烷基、(C6)烷基、(C7)烷基、(C8)烷基、鹵甲基、鹵
乙基、鹵基(C3)烷基、鹵基(C4)烷基、鹵基(C5)烷基、鹵基(C6)烷基、鹵基(C7)烷基、鹵基(C8)烷基、甲基-芳基、乙基-芳基、(C3)烷基-芳基、(C4)烷基-芳基、(C5)烷基-芳基、(C6)烷基-芳基、(C7)烷基-芳基、(C8)烷基-芳基、甲基-(經取代之芳基)、乙基-(經取代之芳基)、(C3)烷基-(經取代之芳基)、(C4)烷基-(經取代之芳基)、(C5)烷基-(經取代之芳基)、(C6)烷基-(經取代之芳基)、(C7)烷基-(經取代之芳基)、(C8)烷基-(經取代之芳基)、O-甲基-芳基、O-乙基-芳基、O-(C3)烷基-芳基、O-(C4)烷基-芳基、O-(C5)烷基-芳基、O-(C6)烷基-芳基、O-(C7)烷基-芳基、O-(C8)烷基-芳基、O-甲基-(經取代之芳基)、O-乙基-(經取代之芳基)、O-(C3)烷基-(經取代之芳基)、O-(C4)烷基-(經取代之芳基)、O-(C5)烷基-(經取代之芳基)、O-(C6)烷基-(經取代之芳基)、O-(C7)烷基-(經取代之芳基)、O-(C8)烷基-(經取代之芳基)、甲基-雜環基、乙基-雜環基、(C3)烷基-雜環基、(C4)烷基-雜環基、(C5)烷基-雜環基、(C6)烷基-雜環基、(C7)烷基-雜環基、(C8)烷基-雜環基、甲基-(經取代之雜環基)、乙基-(經取代之雜環基)、(C3)烷基-(經取代之雜環基)、(C4)烷基-(經取代之雜環基)、(C5)烷基-(經取代之雜環基)、(C6)烷基-(經取代之雜環基)、(C7)烷基-(經取代之雜環基)、(C8)烷基-(經取代之雜環基)、O-甲基-雜環基、O-乙基-雜環基、O-(C3)烷基-雜環基、O-(C4)烷基-雜環基、O-(C5)烷基-雜環基、O-(C6)烷基-雜環基、O-(C7)烷基-雜環基、O-(C8)烷基-雜環基、O-甲基-(經取代之雜環基)、O-乙基-(經取代之雜環基)、O-(C3)烷基-(經取
代之雜環基)、O-(C4)烷基-(經取代之雜環基)、O-(C5)烷基-(經取代之雜環基)、O-(C6)烷基-(經取代之雜環基)、O-(C7)烷基-(經取代之雜環基)及O-(C8)烷基-(經取代之雜環基)。
在本發明之另一實施例中,R17可選自以下中之一或多者之任何組合:H、CH2CF3、環丙基、硫雜環丁烷基、硫雜環丁烷基二氧化物及鹵苯基。
在本發明之另一實施例中,X1為CR12,X2為CR13,且X3為CR9。
在本發明之另一實施例中,雜環基之環結構較佳具有約6至10個原子、更佳6至8個原子。
式I分子通常將具有約100道爾頓(Dalton)至約1200道爾頓之分子質量。然而,在分子質量為約120道爾頓至約900道爾頓時通常較佳,且在分子質量為約140道爾頓至約600道爾頓時通常甚至更佳。
式IV之苯甲醇(其中R1、R2、R3、R4、R5、R6及R7係如先前所揭示)可以兩種方式合成。揭示於流程I之步驟 a 中一種方式係藉由以下方式進行:在0℃下,在極性質子溶劑(諸如甲醇(MeOH))中,在鹼性條件(諸如氫氧化鈉水溶液(NaOH))下,用還原劑(諸如硼氫化鈉(NaBH4))處理式II之酮(其中R1、R2、R3、R4、R5及R6係如先前所揭示)。或者,如流程I之步驟 b 中,使式III之醛(其中R1、R2、R3、R4、R5及R7係如先前所揭示)在催化量之氟化四丁銨(TBAF)存在下在極性非質子溶劑(諸如四氫呋喃(THF))中與三氟三甲基矽烷反應。如流程I之步驟 c 中,式IV化合物可藉由以
下方式轉化成式V化合物(其中Y係選自Br、Cl或I,和R1、R2、R3、R4、R5、R6及R7係如先前所揭示):與鹵化試劑,諸如與N-溴丁二醯亞胺(NBS)及亞磷酸三乙酯在回流溫度下在非反應性溶劑(諸如二氯甲烷(CH2Cl2))中反應,得到Y=Br,或諸如與亞硫醯氯及吡啶在回流溫度下在烴溶劑(諸如甲苯)中反應,得到Y=Cl。
可如流程II、III、IV及V中形成苯乙烯偶合搭配物。
在流程II中,式VI之乙烯基苯甲酸(其中R11為(C=O)OH且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)可在兩個步驟中轉化成式VIIa之乙烯基苯甲醯胺(其中R11為(C=O)N(R14)(R15),且R8、R9、R10、R12、R13、R14、R15及X係如先前所揭示)。如流程II之步驟 d 中,在催化量之N,N-二甲基甲醯胺(DMF)存在下在非反應性溶劑(諸如CH2Cl2)中用乙二醯氯處理式VI之苯甲酸,形成酸氯
化物,隨後使該酸氯化物在鹼(諸如三乙胺(TEA))存在下在極性非質子溶劑(諸如THF)中與胺(HN(R14)(R15))(其中R14及R15係如先前所揭示)反應,得到式VIIa之乙烯基苯甲醯胺(其中R11為(C=O)N(R14)(R15),且R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示),如流程II之步驟 e 中。
在流程III及IV中,式VIII之鹵苯甲酸(其中R18為Br或I,R11為(C=O)OH且R9、R10、R12、R13、X1、X2及X3係如先前所揭示)可轉化成式VIIb1或式VIIb2之乙烯基苯甲酸酯(其中R18為Br或I,R11為(C=O)O(C1-C6烷基),且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。在流程III之步驟 f 中,式VIII之鹵苯甲酸(其中R18為Br)在約-78℃之溫度下在極性非質子溶劑(諸如THF)中用鹼(諸如正丁基鋰(n-BuLi))及DMF處理。如步驟 g 中,使所得甲醯基苯甲酸在醇(諸如乙醇(EtOH))存在下與酸(諸如硫酸(H2SO4))反應,得到式IX之甲醯基苯甲酸乙酯(其中R11為(C=O)O(C1-C6烷基),且R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程III之步驟 h 中,式VIIb1之乙烯
基苯甲酸酯經由式IX化合物在環境溫度下在極性非質子溶劑(諸如1,4-二噁烷)中與鹼(諸如碳酸鉀(K2CO3))及溴化甲基三苯基鏻之反應得到。
在流程IV之步驟i中,在環境溫度下,在極性非質子溶劑(諸如THF)中,在鹼(諸如TEA)及催化量之4-(二甲基胺基)吡啶(DMAP)存在下,用二碳酸二第三丁酯處理式VIII之鹵苯甲酸(其中R18為Br,R11為(C=O)OH,且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如步驟 j 中,使所得苯甲酸第三丁酯在回流溫度下在非反應性溶劑(諸如甲苯)中在鈀催化劑(諸如肆(三苯基膦)鈀(0)(Pd(PPh3)4))及鹼(諸如K2CO3)存在下與乙烯基酸酐吡啶複合物反應,得到式VIIb2之乙烯基苯甲酸酯(其中R11為(C=O)O(C1-C6烷基),且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在流程V之步驟k中,式VIIb2之乙烯基苯甲酸酯(其中R10為Br,R11為(C=O)O(C1-C6烷基),且R8、R9、R12、R13、X1、X2及X3係如先前所定義)可藉由在140℃下在極性非質子溶劑(諸如DMF)中與氰化銅(I)(CuCN)反應而進一步轉化成相應式VIIb3之乙烯基苯甲酸酯(其中R10為CN,R11為(C=O)O(C1-C6烷基),且R8、R9、R12、R13、X1、X2及X3係如先前所揭示)。
式V化合物與式VIIa、VIIb1、VIIb2及VIIb3之化合物之偶合可如流程VI、VII及VIII中實現。在流程VI之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式VIIa之乙烯基苯甲醯胺(其中R11為(C=O)N(R14)(R15),且R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在氯化銅(I)(CuCl)及2,2-聯吡啶存在下反應,得到式I分子(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。
在流程VII之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式VIIb1之乙烯基苯甲酸酯(其中R11為(C=O)O(C1-C6烷基),且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到式Xa化合物(其中R11為(C=O)O(C1-C6烷基),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。式Xa化合物接著藉由如步驟 m 及 n 中所揭示之兩步法或在如步驟 o 中所揭示之一個步驟中轉化成式I分子(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。在流程VII之步驟 m 中,式Xa之酯在約100℃下在極性非質子溶劑(諸如1,4-二噁烷)中在酸性條件(諸如約11當量濃度(N)鹽酸(HCI))下皂化成相應酸。該酸隨後可使用肽偶合試劑,諸如1-羥基苯并三唑(HOBt)、N-(3-二甲基胺基丙基)-N'-乙基-碳化二亞胺鹽酸鹽(EDC.HCl)、六氟磷酸苯并三唑-1-基-氧基三吡咯啶基鏻(PyBOP)、六氟磷酸2-氯-1,3-二甲基咪唑鎓(CIP)、1-羥基-7-氮雜苯并三唑
(HOAt)或O-苯并三唑-N,N,N',N'-四甲基--六氟-磷酸鹽(HBTU),在鹼(諸如N,N-二異丙基乙胺(DIPEA)或DMAP)存在下與胺(HN(R14)(R15))(其中R14及R15係如先前所揭示)偶合,得到式I分子(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。或者,如流程VII之步驟 o 中,使式Xa之酯在三甲基鋁於甲苯中之溶液存在下在非反應性溶劑(諸如CH2Cl2)中在環境溫度下與胺(HN(R14)(R15))反應,得到式I分子(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。
在流程VIII之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式VIIb2或VIIb3之乙烯基苯甲酸酯(其中R11為(C=O)O(C1-C6烷
基),且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到式Xb化合物(其中R11為(C=O)OH,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。式Xb化合物接著在如步驟n中所揭示之一個步驟中轉化成式I分子(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。在流程VIII之步驟 n 中,式Xb之酸可使用肽偶合試劑(諸如HOBt、EDC.HCl、PyBOP、CIP、HOAt或HBTU)在鹼(諸如DIPEA或DMAP)存在下與胺(HN(R14)(R15))(其中R14及R15係如先前所揭示)偶合,得到式I分子(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、R14、R15、X1、X2及X3係如先前所揭示)。
在流程XIII之步驟 t 中,式XIa之氯化乙烯基苯甲基(其中R11為-CH2Cl且R8、R9、R10、R12、R13、X1、X2及X3係如先前所定義)可藉由在70℃下在極性非質子溶劑(諸如DMF)中與鄰苯二甲醯亞胺鉀反應而轉化成相應式XIIa之經鄰苯二甲醯亞胺保護之苯甲胺(其中R11為CH2N(鄰苯二甲醯亞胺),且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在流程XIV之步驟 u 中,式XIIIa之4-甲基苯甲腈(其中R11為CH3且R9、R10、R12、R13、X1、X2及X3係如先前所定義)可藉由在77℃下在非反應性溶劑(諸如四氯化碳(CCl4))中與NBS及偶氮二異丁腈(AIBN)反應而轉化成相應式XIVa之溴甲苯(其中R11為CH2Br且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XIV之步驟 v 中,式XIVa之氰基(CN)可經由在0℃下在非質子溶劑(諸如甲苯)中與氫化二異丁基鋁(DIBAL-H)反應,隨後用1.0M HCl淬滅而還原成相應式XVa之醛(其中R11為CH2Br且R9、R10、R12、R13、X1、X2及X3係如先前所定義)。如流程XIV之步驟 t 中,式XVa化合物可藉由在60℃下在極性非質子溶劑(諸如DMF)中與鄰苯二甲醯亞胺鉀反應而進一步轉化
成相應式XVIa之經鄰苯二甲醯亞胺保護之苯甲胺(其中R11為CH2N(鄰苯二甲醯亞胺)且R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。在流程XIV之步驟 w 中,式XVIa之醛可藉由在環境溫度下在鹼(諸如K2CO3)存在下在極性非質子溶劑(諸如1,4-二噁烷)中與溴化甲基三苯基鏻反應而轉化成式XIIb之烯烴(其中R11為CH2N(鄰苯二甲醯亞胺)且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
如流程XV之步驟 x 中,式XVa之醛(其中R11為CH2Br且R9、R10、R12、R13、X1、X2及X3係如先前所定義)可在環境溫度下在鹼(諸如K2CO3)存在下在極性非質子溶劑(諸如N,N-二甲基乙醯胺(DMA))中與親核試劑(諸如2-胺基吡啶)反應,得到式XVII化合物(其中R11為CH2NH(2-吡啶)且R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。在流程XV之步驟 w 中,式XVII化合物可轉化成式XVIII之烯烴(其中R11為CH2NH(2-吡啶)且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在兩步中,如流程XVI之步驟 y 及 z 中之一鍋式反應,式XIX化合物可在環境溫度下在鹼(諸如氫化鈉(NaH))及極性非質子溶劑(諸如DMF)存在下與式XX化合物(其中R10及R11為Cl,X1為N,且R9、R13、X2及X3係如先前所揭示)反應,得到式XXI化合物(其中R10為Cl,R11為(CH)NH2CO2CH2CH3,X1為N,且R9、R13、X2及X3係如先前所定義)。如在流程XVI之步驟 aa 中,式XXI化合物之水解及脫羧可伴隨在回流溫度下在酸性條件下(諸如在3N HCl情況下)之反應,得到式XXII化合物(其中R10為Cl,R11為CH2NH2.HCl,X1為N,且R9、R13、X2及X3係如先前所揭示)。如流程XVI之步驟 ab 中,式XXII化合物可藉由在回流溫度下在鹼(諸如TEA)及非質子溶劑(諸如甲苯)存在下與鄰苯二甲酸酐反應而進一步轉化成相應式XXIIIa之經鄰苯二甲醯亞胺保護之苯甲胺(其中R10為Cl,R11為CH2N(鄰苯二甲醯亞胺),X1為N,且R9、R13、X1、X2及X3係如先前所揭示)。如流程XVI之步驟 ac 中,式XXIIIa之溴化物可藉由在回流溫度下在非反應性溶劑(諸如甲苯)中在鈀催化劑(諸如Pd(PPh3)4)及鹼(諸如K2CO3)存在下與乙烯基酸酐吡啶複合物反應而轉化成式XIIc之烯烴(其中R10為Cl,R11為CH2N(鄰苯二甲醯亞胺),X1為N,且R8、R9、R13、X2
及X3係如先前所揭示)。
在流程XVII之步驟 u 中,式XIIIb之4-甲基萘甲腈(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH3,且R12、R13、X1及X2係如先前所定義)可藉由在77℃下在非反應性溶劑(諸如CCl4)中與NBS及AIBN反應而轉化成相應式XIVb之溴化萘(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2Br,且R12、R13、X1及X2係如先前所揭示)。如流程XVII之步驟 v 中,式XIVb之氰基(CN)可經由在0℃下在非質子溶劑(諸如甲苯)中與氫化二異丁基鋁(DIBAL-H)反應,隨後用1.0M HCl淬滅而還原成相應式XVb之醛(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環(或必要時為非芳環),R11為CH2Br,且R12、R13、X1及X2係如先前所定義)。如流程XVII之步驟 t 中,式XVb化合物可藉由在60℃下在極性非質子溶劑(諸如DMF)中與鄰苯二甲醯亞胺鉀反應而進
一步轉化相應式XVIb之經鄰苯二甲醯亞胺保護之苯甲胺(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2N(鄰苯二甲醯亞胺),且R12、R13、X1及X2係如先前所揭示)。在流程XVII之 w 步驟中,式XVIb之醛可藉由在環境溫度下在鹼(諸如K2CO3)存在下在極性非質子溶劑(諸如1,4-二噁烷)中與溴化甲基三苯基鏻反應而轉化成式XIId之烯烴(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2N(鄰苯二甲醯亞胺),且R8、R12、R13、X1及X2係如先前所揭示)。
如流程XVIII之步驟 ad 中,式XXIV化合物(其中R11為NHNH2.HCl且R9、R10、R12、R13、X1、X2及X3係如先前所揭示)可藉由在回流溫度下在冰乙酸(AcOH)中與鄰苯二甲酸酐反應而轉化成相應式XXV之經鄰苯二甲醯亞胺保護之肼(其中R11為NHN(鄰苯二甲醯亞胺)且R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XVIII
之步驟 ae 中,式XXV之溴化物可藉由在微波條件下在150℃下在極性非質子溶劑(諸如1,2-二甲氧基乙烷)中在鈀催化劑(諸如Pd(PPh3)4)及鹼(諸如K2CO3)存在下與乙烯基酸酐吡啶複合物反應而轉化成式XIIe之烯烴(其中R11為NHN(鄰苯二甲醯亞胺)且R8、R9、R10、R13、X1,X2及X3係如先前所揭示)。
在流程XIX之步驟 af 中,使式XXVI化合物(其中R11為B(OH)2,且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)在環境溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及吡啶存在下與2-羥基異吲哚啉-1,3-二酮反應,得到式XIIf化合物(其中R11為ON(鄰苯二甲醯亞胺)且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在流程XX之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XIIa化合物(其中R11為CH2N(鄰苯二甲醯亞胺)且R8、R9、R10、
R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式XXVIIa化合物(其中R11為CH2N(鄰苯二甲醯亞胺)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XX之步驟 ag 中,式XXVIIa化合物中之鄰苯二甲醯亞胺保護基藉由在90℃下在極性質子溶劑(諸如EtOH)中與水合肼反應來移除,得到式XXVIIIa化合物(其中R11為CH2NH2且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XX之步驟 ah 1 中,式XXVIIIa化合物可藉由在0℃下在非反應性溶劑(諸如CH2Cl2)中用酸酐(諸如乙酸酐)及鹼(諸如TEA)醯化而轉化成式I化合物(其中R11為CH2N(C=O)(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在流程XXI之步驟 l 中,使式V化合物(其中Y、
R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XIIb化合物(其中R11為CH2N(鄰苯二甲醯亞胺)且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式XXVIIb化合物(其中R11為CH2N(鄰苯二甲醯亞胺)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XXI之步驟 ag 中,式XXVIIb化合物中之鄰苯二甲醯亞胺保護基藉由在90℃下在極性質子溶劑(諸如EtOH)中與水合肼反應來移除,得到式XXVIIIb化合物(其中R11為CH2NH2且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XXI之步驟 ah 2a 中,式XXVIIIb化合物可藉由在極性非質子溶劑(諸如DMF)中在HOBt.H2O、EDC.HCl及鹼(諸如DIPEA)存在下與酸反應而轉化成式I化合物(其中R11為CH2N(C=O)(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在另一實施例中,如流程XXI之步驟 ah 2 中,式XXVIIIb化合物可藉由在極性非質子溶劑(諸如DMF)中在HOBt.H2O、EDC.HCl及鹼(諸如DIPEA)存在下與硫代酸反應而轉化成式I化合物(其中R11為CH2N(C=S)(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在另一實施例中,式XXVIIIb化合物可在兩個步
驟中轉化成式I化合物(其中R11為CH2N(C=O)N(R14)(R15)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。第一步驟(流程XXI之步驟 ah 3a )涉及在極性質子溶劑(諸如MeOH)中與醛反應,隨後與NaBH4反應。第二步驟(流程XXI之步驟 ah 3b )涉及在流程XXI之環境溫度下在非反應性溶劑(諸如CH2Cl2)中用酸氯化物(諸如環丙基羰基氯)及鹼(諸如TEA)醯化。
在另一實施例中,式XXVIIIb化合物可藉由在0℃下在鹼(諸如TEA)存在下及在非反應性溶劑(諸如CH2Cl2)中與異氰酸酯(流程XXI之步驟 ai 1 )或胺基甲醯氯(流程XXI之步驟 ai 2 )反應而轉化成式I化合物(其中R11為CH2N(C=O)N(R14)(R15)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在另一實施例中,如流程XXI之步驟 aj 中,式XXVIIIb化合物可藉由在0℃下在鹼(諸如TEA)存在下及在非反應性溶劑(諸如CH2Cl2)中與異硫氰酸酯反應而轉化成式I化合物(其中R11為CH2N(C=S)N(R14)(R15)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在另一實施例中,如流程XXI之步驟 ak 中,式XXVIIIb化合物可藉由在環境溫度下在鹼(諸如TEA)存在下及在非反應性溶劑(諸如CH2Cl2)中與二碳酸酯(諸如二碳酸二第三丁酯)反應而轉化成式I化合物(其中R11為CH2N(C=O)O(R14)且R1、R2、R3、R4、R5、R6、R7、R8、
R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在另一實施例中,如流程XXI之步驟 al 中,式XXVIIIb化合物可藉由在0℃下在鹼(諸如TEA)存在下及在非反應性溶劑(諸如CH2Cl2)中與氯乙二酸酯(諸如2-氯-2-側氧基乙酸酯)反應而轉化成式I化合物(其中R11為CH2N(C=O)(C=O)O(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
在流程XXII之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XIIc化合物(其中R10為Cl,R11為CH2N(鄰苯二甲醯亞胺),X1為N,且R8、R9、R12、R13、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式XXVIIc化合物(其中R10為Cl,R11為CH2N(鄰苯二甲醯亞胺),X1為N,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X2及X3係如先前所揭示)。如流程XXII之步驟 ag 中,式XXVIIc化合物
中之鄰苯二甲醯亞胺保護基藉由在90℃下在極性質子溶劑(諸如EtOH)中與水合肼反應來移除,得到式XXVIIIc化合物(其中R10為Cl,R11為CH2NH2,X1為N,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X2及X3係如先前所揭示)。如流程XXII之步驟 ah 2b 中,式XXVIIIc化合物可藉由在極性非質子溶劑(諸如CH2Cl2)中在HOBt.H2O、EDC.HCl及鹼(DIPEA)存在下與酸反應而轉化成式I化合物(其中R10為Cl,R11為CH2N(C=O)(R14),X1為N,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X2及X3係如先前所揭示)。
在流程XXIII之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XIId化合物(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環(或必要時為非芳環),R11為CH2N(鄰苯二甲醯亞胺)且R8、R9、R12、R13、X1及X2係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)
中在CuCl及2,2-聯吡啶存在下反應,得到相應式XXVIId化合物(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2N(鄰苯二甲醯亞胺)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X1及X2係如先前所揭示)。如流程XXIII之步驟 ag 中,式XXVIId化合物中之鄰苯二甲醯亞胺保護基藉由在90℃下在極性質子溶劑(諸如EtOH)中與水合肼反應來移除,得到式XXVIIId化合物(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2NH2且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X1及X2係如先前所揭示)。如流程XXIII之步驟 ah 2b 中,式XXVIIId化合物可藉由在極性非質子溶劑(諸如CH2Cl2)中在HOBt.H2O、EDC.HCl及鹼(諸如DIPEA)存在下與酸反應而轉化成式I化合物(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2N(C=O)(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X1及X2係如先前所揭示)。
在另一實施例中,如流程XXIII之步驟 ai 1 中,式XXVIIId化合物可藉由在0℃下在鹼(諸如TEA)存在下及在非反應性溶劑(諸如CH2Cl2)中與異氰酸酯反應而轉化成式I化合物(其中X3為CR9,R10及X3共同形成具有4個碳原子之鍵且與環碳原子形成6員芳環,R11為CH2N(C=O)N(R14)(R15)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1及X2係如先前所揭示)。
在流程XXIV之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XIIe化合物(其中R11為NHN(鄰苯二甲醯亞胺)且R8、R9、R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式XXVIIe化合物(其中R11為NHN(鄰苯二甲醯亞胺)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X1、X2及X3係如先前所揭示)。如流程XXIV之步驟 ag 中,式XXVIIe化合物中之鄰苯二甲醯亞胺保護基藉由在90℃下在極性質子溶劑(諸如EtOH)中與水合肼反應來移除,得到式XXVIIIe化合物(其中R11為NHNH2且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X1、X2及X3係如先前所揭示)。如流程XXIV之步驟 ah 2b 中,式XXVIIIe化合物可藉由在極性非質子溶劑(諸如CH2Cl2)中在HOBt.H2O、EDC.HCl及鹼(諸如DIPEA)存在下與酸反應而轉化成式I化合物(其中R11為NHN(C=O)(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R12、R13、X1、X2及X3係如先前所揭示)。
在流程XXV之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XIIf化合物(其中R11為ON(鄰苯二甲醯亞胺)且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式XXVIIf化合物(其中R11為ON(鄰苯二甲醯亞胺)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XXV之步驟 ag 中,式XXVIIf化合物中之鄰苯二甲醯亞胺保護基藉由在90℃下在極性質子溶劑(諸如EtOH)中與水合肼反應來移除,得到式XXVIIIf化合物(其中R11為ONH2且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。如流程XXV之步驟 ah 2b 中,式XXVIIIf化合物可藉由在極性非質子溶劑(諸如CH2Cl2)中在HOBt.H2O、EDC.HCl及鹼(諸如DIPEA)存在下與酸反應而轉化成式I化合物(其中R11為ON(C=O)(R14)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及
X3係如先前所揭示)。
在流程XXVI之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XVIII化合物(其中R11為CH2NH(2-吡啶)且R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式I化合物(其中R11為CH2NH(2-吡啶)且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R12、R13、X1、X2及X3係如先前所揭示)。
式I化合物可利用標準方法進一步精製。舉例而言,當R11含有硫醚時,硫醚可藉由在環境溫度下在丙酮:水混合物存在下用過硫酸氫鉀(oxone)處理來氧化成碸。當R11含有乙二酸酯時,式I化合物可藉由在非反應性溶劑(諸如CH2Cl2)中與胺鹽酸鹽以及三甲基鋁於甲苯中之溶液反應而轉化成相應乙二醯胺。
在流程XXVII中,如步驟 aj 中,式XXIX之氟苯甲醛(其中R10、X1、X2及X3係如先前所揭示)可藉由在溶劑(諸如DMF)中在鹼(諸如K2CO3)存在下與經取代或未經取代之1,2,4-三唑反應而轉化成式XXX之(1,2,4-三唑-1-基)苯甲醛(其中R11為經取代或未經取代之1,2,4-三唑-1-基,且R10、X1、X2及X3係如先前所揭示)。在步驟 ak 中,式XXX之(1,2,4-三唑-1-基)苯甲醛藉由在非質子溶劑(諸如1,4-二噁烷)中在鹼(諸如K2CO3)存在下與溴化三苯基鏻反應而轉化成式XXXIa之(1,2,4-三唑-1-基)乙烯基苯(其中R11為經取代或未經取代之1,2,4-三唑-1-基,且R8、R10、X1、X2及X3係如先前所揭示)。
在流程XXVIII中,式XXXII之溴氟苯(其中R10、X1、X2及X3係如先前所揭示)可在兩個步驟中轉化成式XXXIb之(1,2,4-三唑-1-基)乙烯基苯(其中R11為經取代或未
經取代之1,2,4-三唑-1-基,且R8、R10、X1、X2及X3係如先前所揭示)。在步驟 al 中,溴氟苯在溶劑(諸如DMF)中在鹼(諸如K2CO3)存在下與經取代或未經取代之1,2,4-三唑反應,產生(1,2,4-三唑-1-基)溴苯。在步驟 cl 中,(1,2,4-三唑-1-基)溴苯在溶劑(諸如甲苯)中在催化劑(諸如Pd(PPh3)4)及鹼(諸如K2CO3)存在下與乙烯基酸酐吡啶複合物反應。
式V化合物與式XXXIa及XXXIb之化合物之偶合可如流程XXIX中實現。在步驟 l 中,使式V化合物(其中Y為Br,R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XXXIa或XXXIb之乙烯基苯(其中R11為經取代或未經取代之1,2,4-三唑-1-基,且R8、R9、R10、X1、X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到式I分子(其中R11為經取代或未經取代之1,2,4-三唑-1-基,且R1、R2、R3、R4、R5、R6、R7、R8、R10、X1、X2及X3係如先前所揭示)。
在流程XXX中,式XXXIII化合物(其中R11為3-硝基-1,2,4-三唑-1-基,且R1、R2、R3、R4、R5、R6、R7、R8、R10、X1、X2及X3係如先前所揭示)可利用兩步法轉化成式I化合物(其中R11為3-醯胺基-1,2,4-三唑-1-基,且R1、R2、R3、R4、R5、R6、R7、R8、R10、X1、X2及X3係如先前所揭示)。在步驟 am 中,3-硝基-1,2,4-三唑-1-基在質子溶劑(諸如MeOH)中在鋅粉及氯化銨(NH4Cl)存在下還原成3-胺基-1,2,4-三唑-1-基。在步驟 an 中,3-胺基-1,2,4-三唑-1-基在溶劑(諸如CH2Cl2)中在鹼(諸如TEA)存在下用酸氯化物(諸如環丙基羰基氯或乙醯氯)醯化。
在流程XXXI之步驟 ao 中,式XXXIV之溴苯基甲基酮(其中R10、X1、X2及X3係如先前所揭示)藉由在溶劑(諸如DMF)中在鹼(諸如碳酸銫(Cs2CO3))及催化劑(諸如碘化銅(CuI))存在下用1,2,4-三唑處理而轉化成式XXXV之苯
基甲基酮(其中R11為1,2,4-三唑-1-基,且R10、X1、X2及X3係如先前所揭示)。在步驟 ap 中,式XXXV之1,2,4-三唑基苯乙酮藉由在非質子溶劑(諸如CH2Cl2)中在鹼(諸如TEA)存在下用三氟甲磺酸三甲基矽烷酯處理而轉化成式XXXVI之三甲基矽烷基烯醇醚。在步驟 aq 中,矽烷基烯醇醚與式V化合物(其中Y為Br,R1、R2、R3、R4、R5、R6及R7係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,產生式XXXVII之酮(其中R11為1,2,4-三唑-1-基,且R1、R2、R3、R4、R5、R6、R7、R10、X1、X2及X3係如先前所揭示)。在步驟 ar 中,式XXXVII之酮在非質子溶劑(諸如THF)中用溴化甲基鎂處理,產生三級醇。接著,如步驟 as 中,三級醇在用催化量之對甲苯磺酸在溶劑(諸如甲苯)中處理時,在經加熱達至允許共沸移除水之溫度時經歷消除反應,產生式I化合物(其中R11為1,2,4-三唑-1-基,R8為甲基,且R1、R2、R3、R4、R5、R6、R7、R10、X1、X2及X3係如先前所揭示)。
在流程XXXII中,式XXXVIII化合物(其中R10及R11共同形成具有3-4個碳原子及側氧基取代基之鍵且與環碳原子形成5員或6員環,且R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)藉由在溶劑(諸如1,2-二氯乙烷(DCE))中在還原劑(諸如氰基硼氫化鈉(NaBH3CN))存在下用烷基胺(諸如3,3,3-三氟丙胺)處理而轉化成式I分子(其中R10及R11共同形成具有3-4個碳原子及烷基胺取代基之鍵,與環碳原子形成5員或6員環,且R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。
在流程XXXIII中,如步驟 au 中,式XXXIX化合物(其中X1、X2及X3係如先前所揭示)藉由在溶劑(諸如AcOH)中用還原劑(諸如NaBH3CN)處理而轉化成式XL分子(其中X1、X2及X3係如先前所揭示)。在步驟 av 中,氮原子藉由在溶劑(諸如乙腈(MeCN))中在催化劑(諸如DMAP)存在下與二碳酸二第三丁酯反應而用第三丁氧基羰基(BOC)保護。如步驟 aw 中,式XL之溴化物可藉由在100℃下在極性非質子溶劑(諸如二甲亞碸(DMSO))中在鈀催化劑(諸如PdCl2(dppf))及鹼(諸如K2CO3)存在下與乙烯基三氟硼酸鉀反應而轉化成式XLI之烯烴(其中R8、X1,X2及X3係如先前所揭示)。
在流程XXXIV中,式XXXIX化合物(其中X1、X2及X3係如先前所揭示)在兩個步驟中轉化成式XLII分子(其中X1、X2及X3係如先前所揭示)。在步驟 ax 中,烯烴藉由
在溶劑混合物(諸如THF/水)中在鈀催化劑(諸如PdCl2)及配位體(諸如三苯基膦)及鹼(諸如Cs2CO3)存在下用乙烯基三氟硼酸鉀處理溴化物而形成。在步驟 ay 中,氮原子藉由在溶劑(諸如MeCN)中在催化劑(諸如DMAP)存在下與二碳酸二第三丁酯反應而用BOC基團保護。
在流程XXXV之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式XLI或XLII之化合物(其中R8、X1,X2及X3係如先前所揭示)在約150℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式XLIIIa或XLIIIb之化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。
在流程XXXVI中,如步驟 az 中,式XLIIIa化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3
係如先前所揭示)藉由在溶劑(諸如CH2Cl2)中用三氟乙酸(TFA)處理而轉化成式XLIV分子(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。式XLIV化合物接著可在兩個步驟中轉化成式XLV化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。在步驟 ba 中,吲哚啉在約5℃之溫度下在酸(諸如濃HCl)中用亞硝酸鈉(NaNO2)處理,形成亞硝基吲哚。在步驟 bb 中,亞硝基吲哚在質子溶劑(諸如MeOH)中在鋅粉存在下與NH4Cl反應。在步驟 bc 中,式XLV化合物藉由在極性非質子溶劑(諸如CH2Cl2)中處理一酸(諸如3,3,3-三氟丙酸)、PyBOP及一鹼(諸如DIPEA)而轉化成式XLVI化合物(其中X4為N(R14)(C(=O)R14)且R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。
在流程XXXVII中,如步驟 bd 中,式XLIIIb化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及
X3係如先前所揭示)藉由在溶劑(諸如CH2Cl2)中用TFA處理而轉化成式XLVII之吲哚(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。如步驟 be 中,式XLVII化合物可藉由在溶劑(諸如MeCN)中在氟化鉀(KF)及冠醚(諸如18-冠-6-醚)存在下與4-硝基苯基-2-((第三丁氧基羰基)胺基)乙酸酯反應而轉化成式XLVIII化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。式XLVIII化合物可在兩個步驟中轉化成式XLIX化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。在步驟 bf 中,Boc基團藉由在溶劑(諸如CH2Cl2)中用TFA處理來移除。在步驟 bg 中,胺在極性非質子溶劑(諸如CH2Cl2)中用3,3,3-三氟丙酸、PyBOP及鹼(諸如DIPEA)處理。
在流程XXXVIII中,如步驟 bh 中,式L化合物(其中X1、X2及X3係如先前所揭示)藉由在鹼(諸如NaOH)中用
五水合硫酸銅(II)及Zn粉處理而轉化成式LI化合物(其中X1、X2及X3係如先前所揭示)。如步驟 bi 中,式LI化合物可藉由在約95℃之溫度下在溶劑(諸如水)中與肼反應而轉化成式LII化合物(其中X1、X2及X3係如先前所揭示)。在步驟 bj 中,式LIII之烯烴(其中X1、X2及X3係如先前所揭示)藉由在溶劑混合物(諸如DMSO)中在鈀催化劑(諸如PdCl2(dppf))及鹼(諸如K2CO3)存在下用乙烯基三氟硼酸鉀處理溴化物而形成。式LIV化合物(其中X1、X2及X3係如先前所揭示)可藉由在溶劑(諸如DMF)中在鹼(諸如Cs2CO3)存在下與溴乙酸乙酯反應而由式LIII化合物形成。
在流程XXXIX之步驟 l 中,使式V化合物(其中Y、R1、R2、R3、R4、R5、R6及R7係如先前所揭示)與式LIV化合物(其中R8、X1,X2及X3係如先前所揭示)在約180℃之溫度下在溶劑(諸如1,2-二氯苯)中在CuCl及2,2-聯吡啶存在下反應,得到相應式LV化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。式
LV化合物可在兩個步驟中進一步轉化成式LVI化合物(其中R1、R2、R3、R4、R5、R6、R7、R8、X1、X2及X3係如先前所揭示)。在步驟 bl 中,酯在約100℃之溫度下在HCl及AcOH存在下水解成酸。在步驟 bm 中,酸在極性非質子溶劑(諸如CH2Cl2)中用胺(諸如2,2,2-三氟乙胺)、PyBOP及鹼(諸如DIPEA)處理。
在流程XL之步驟 bn 中,使式LVII之羧酸(其中R11為C(=O)OH且R8、R10、X1、X2及X3係如先前所揭示)與式V化合物(其中Y為Br且R1、R2、R3、R4、R5、R6及R7係如先前所揭示)在約150℃之溫度下在溶劑(諸如N-甲
基吡咯啶)中在CuCl及2,2-聯吡啶存在下反應,得到式LVIII化合物(其中R11為(C=O)OH且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X1、X2及X3係如先前所揭示)。如步驟 bo 中,式LVIII化合物可藉由在極性非質子溶劑(諸如CH2Cl2)中用胺(諸如2-胺基-N-(2,2,2-三氟乙基)乙醯胺)、PyBOP及鹼(諸如DIPEA)處理而轉化成相應式LIX之苯甲醯胺(其中R11為(C=O)N(R14)(R15),且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X1、X2及X3係如先前所揭示)。
實例出於說明目的而不應解釋為將本文件中揭示之發明限制為僅此等實例中揭示之實施例。
自商業來源獲得之起始物質、試劑及溶劑在未進一步純化情況下使用。無水溶劑自Aldrich以Sure/SealTM購得且按原樣使用。熔點在Thomas Hoover Unimelt毛細管熔點裝置或來自Stanford Research Systems之OptiMelt自動熔
點系統上獲得且為未校正的。分子以其已知名稱給出,該等名稱根據ISIS Draw、ChemDraw或ACD Name Pro中之命名程式來命名。若該等程式不能命名分子,則該分子使用習知命名規則來命名。除非另有說明,否則1H NMR光譜資料以ppm(δ)為單位且在300MHz、400MHz或600MHz記錄,且13C NMR光譜資料以ppm(δ)為單位且在75MHz、100MHz或150MHz記錄。
步驟1方法A. 1-(3,5-二氯苯基)-2,2,2-三氟乙醇(AI2). 在0℃下向經攪拌之1-(3,5-二氯苯基)-2,2,2-三氟乙酮(自Rieke Metals,UK獲得;5.0公克(g),20.5毫莫耳(mmol))於MeOH(100毫升(mL))中之溶液中添加NaBH4(3.33g,92.5mL)及1N NaOH水溶液(10mL)。將反應混合物溫至25℃且攪拌2小時(h)。在利用薄層層析法(TLC)認為反應完全之後,將NH4Cl飽和水溶液添加至反應混合物中,且在減壓下濃縮混合物。殘餘物用乙醚(Et2O)稀釋且用水(3×50mL)洗滌。有機層經硫酸鈉(Na2SO4)乾燥且在減壓下濃縮,得到呈液體狀之標題化合物(4.0g,79%):1H NMR(400MHz,CDCl3)δ 7.41(m,3H),5.00(m,2H),2.74(s,1H);ESIMS m/z 242.97([M-H]-)。
步驟1方法B. 1-(3,5-二氯苯基)-2,2,2-三氟乙醇 (AI2). 向經攪拌之3,5-二氯苯甲醛(10g,57mmol)於THF(250mL)中之溶液中添加三氟甲基三甲基矽烷(9.79g,69.2mmol)及催化量之TBAF。在25℃下攪拌反應混合物8h。在利用TLC認為反應完全之後,反應混合物用3N HCl稀釋且將其接著攪拌16h。反應混合物用水稀釋且用乙酸乙酯(EtOAc;3×)萃取。合併之有機萃取物用鹽水洗滌,經Na2SO4乾燥,且在減壓下濃縮,得到呈液體狀之標題化合物(8.41g,60%)。
以下化合物根據上文實例1之步驟1方法A中揭示之程序製造。
2,6-二氟-4-(2,2,2-三氟-1-羥乙基)苯甲腈
產物以棕色固體狀分離:mp 83-87℃;1H NMR(300MHz,CDCl3)δ 7.26(d,J=9.0Hz,2H),5.12(d,J=6.0Hz,1H),3.06(s,1H);ESIMS m/z 237.1([M+H]+)。
1-(3,5-二氟-4-甲氧基苯基)-2,2,2-三氟乙醇
產物以淺黃色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.06(d,J=8.4Hz,2H),4.97-4.94(m,1H),4.03(s,3H),2.64(s,1H);EIMS m/z 242.1([M]+);IR(薄膜)3459,
1135cm-1。
1-(3,4-二氯苯基)-2,2-二氟丙-1-醇
產物以無色液體狀分離:1H NMR(300MHz,DMSO-d6)δ 7.65-7.62(m,2H),7.41(d,J=8.4Hz,1H),6.49(d,J=5.1Hz,1H),4.87-4.78(m,1H),1.53(t,J=18.9Hz,3H);EIMS m/z 240.0([M]+);IR(薄膜)3434,1131,801,512cm-1。
以下化合物根據上文實例1之步驟1方法B中揭示之程序製造。
2,2,2-三氟-1-(3,4,5-三氯苯基)乙醇(AI3)
產物以淺黃色液體狀分離(500mg,65%):1H NMR(400MHz,CDCl3)δ 7.45(s,2H),5.00(m,1H),2.80(s,1H);ESIMS m/z 278([M+H]+);IR(薄膜)3420,1133,718cm-1。
1-(3,5-二氯-4-氟苯基)-2,2,2-三氟乙醇(AI4)
產物以淺黃色液體狀分離(500mg,65%):1H
NMR(400MHz,CDCl3)δ 7.41(s,2H),5.00(m,1H),2.80(s,1H);ESIMS m/z 262([M+H]+);IR(薄膜)3420,1133,718cm-1。
1-(3,4-二氯苯基)-2,2,2-三氟乙醇(AI5)
產物以淺黃色液體狀分離(500mg,65%):1H NMR(400MHz,CDCl3)δ 7.60(s,1H),7.51(m,1H),7.35(m,1H),5.01(m,1H),2.60(s,1H);EIMS m/z 244([M]+)。
1-(3,5-二溴苯基)-2,2,2-三氟乙醇
標題分子以無色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.67(s,1H),7.58(s,2H),5.08-5.02(m,1H),4.42(bs,1H);EIMS m/z 333.7([M]+);IR(薄膜)3417,2966,1128,531cm-1。
2,2,2-三氟-1-(3-氟-5-(三氟甲基)苯基)乙醇
標題分子以澄清無色油狀物分離:1H NMR(400MHz,CDCl3)δ 7.56(s,1H),7.45-7.37(m,2H),5.11(q,J=6.4Hz,1H),3.22(bs,1H);13C NMR(101MHz,CDCl3)δ
162.42(d,J=249.5Hz),137.46(d,J=7.8Hz),132.89(qd,J=33.5,7.9Hz),123.67(q,J=283.8Hz),122.92(q,J=270.68Hz),120.10(t,J=4.1Hz),118.13(d,J=23.0Hz),113.94(dq,J=24.2,3.9Hz),71.57(q,J=32.4Hz);EIMS m/z 262([M]+)。
1-(3-氯-5-(三氟甲基)苯基)-2,2,2-三氟乙醇
產物以白色固體狀分離(4.98g,77%):mp 42-46℃;1H NMR(400MHz,CDCl3)δ 7.83-7.50(m,3H),5.10(p,J=6.2Hz,1H),2.88(d,J=4.3Hz,1H);13C NMR(101MHz,CDCl3)δ 137.12,135.84,131.4,133.03(q,J=33.3Hz),127.15(q,J=3.8Hz),124.50(q,J=308.0Hz),123.45(q,J=301.8Hz),123.04,72.06(q,J=32.5Hz);19F NMR(376MHz,CDCl3)δ -62.93,-78.43;EIMS m/z 278([M]+)。
2,2,2-三氟-1-(4-氟-3-(三氟甲基)苯基)乙醇
產物以棕色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.76(d,J=6.8Hz,1H),7.69-7.67(m,1H),7.28-7.23(m,1H),5.05-5.02(m,1H);ESIMS m/z 261.1
([M-H]-);IR(薄膜)3418,1131cm-1。
2,2,2-三氟-1-(3,4,5-三氟苯基)乙醇
產物以無色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.19-7.10(m,2H),5.03-4.96(m,1H),2.85(bs,1H);EIMS m/z 230.1([M]+)。
2,2,2-三氟-1-(2,3,4-三氟苯基)乙醇
產物以澄清無色液體狀分離(4.61g66%):1H NMR(400MHz,CDCl3)δ 7.23(qd,J=7.4,6.1,4.2Hz,1H),6.93(tdd,J=9.2,6.9,2.2Hz,1H),5.25(q,J=6.3Hz,1H),3.02-2.74(m,1H);13C NMR(101MHz,CDCl3)δ 151.79(ddd,J=254.5,9.8,3.4Hz),149.52(ddd,J=253.5,11.0,3.5Hz),139.67(dt,J=252.5,15.3Hz),123.68(q,J=282.2Hz),122.48(dt,J=8.2,4.1Hz),118.95(dd,J=10.6,3.6Hz),112.73(dd,J=17.7,3.9Hz),66.58-64.42(m);19F NMR(376MHz,CDCl3)δ -78.95(d,J=6.2Hz),-132.02(dd,J=20.0,8.2Hz),-137.89(m),159.84(t,J=20.3Hz);EIMS m/z 230([M]+)。
2,2,2-三氟-1-(2,4,5-三氯苯基)乙醇
產物以白色固體狀分離(3.37g,73%):mp 70-73℃;1H NMR(400MHz,CDCl3)δ 7.63(d,J=2.5Hz,1H),7.54(d,J=2.5Hz,1H),5.72-5.57(m,1H),2.85(d,J=4.8Hz,1H);19F NMR(376MHz,CDCl3)δ -77.84。
1-(4-氯-3-硝基苯基)-2,2,2-三氟乙醇
產物以黃色油狀物分離(6.52g,73%):1H NMR(400MHz,CDCl3)δ 8.04(d,J=2.0Hz,1H),7.75-7.51(m,2H),5.16(m,1H),3.41(d,J=4.3Hz,1H);13C NMR(101MHz,CDCl3)δ 147.65,134.44,132.23,132.17,128.11,124.66,123.60(q,J=283.8),70.99(q,J=32.6Hz);19F NMR(376MHz,CDCl3)δ -78.47;EIMS m/z 230([M]+)。
2,2,2-三氟-1-(4-氟-3,5-二甲基苯基)乙醇
產物以白色固體狀分離(6.49g,84%):mp 45-49℃;1H NMR(400MHz,CDCl3)δ 7.10(d,J=6.8Hz,2H),4.89(m,1H),2.63(d,J=4.3Hz,1H),2.27(d,J=2.2
Hz,6H);13C NMR(101MHz,CDCl3)δ 160.45(d,J=246.0Hz),128.73,127.97,124.92(d,J=18.6Hz),124.19(q,J=279.1Hz),72.36(q,J=32.0Hz),14.61(d,J=4.1Hz)。
19F NMR(376MHz,CDCl3)δ -78.48,-120.14;EIMS m/z 222([M]+)。
2,2,2-三氟-1-(4-氟-3-甲基苯基)乙醇
產物以白色固體狀分離(2.12g,33%):mp 40-46℃;1H NMR(400MHz,CDCl3)δ 7.28(d,J=7.4Hz,1H),7.25-7.14(m,1H),7.01(t,J=8.9Hz,1H),5.05-4.63(m,1H),3.03(d,J=4.2Hz,1H);13C NMR(101MHz,CDCl3)δ 161.91(d,J=247.0Hz),130.62(d,J=5.6Hz),129.41(d,J=3.5Hz),126.55(d,J=8.5Hz),115.19(d,J=22.9Hz),72.23(q,J=32.1Hz),14.44(d,J=3.6Hz);19F NMR(376MHz,CDCl3)δ -78.57,-116.15;EIMS m/z 208([M]+)。
1-(3-氯-4-甲基苯基)-2,2,2-三氟乙醇
產物以澄清無色油狀物分離(4.99g,75%):1H NMR(400MHz,CDCl3)δ 7.31(s,1H),7.10(m,2H),4.79(q,J=6.1Hz,1H),2.89(bs,1H),2.25(s,3H);13C NMR(101MHz,CDCl3)δ 137.64,134.67,132.99,131.09,128.01,125.58,124.02(q,J=284.8Hz),72.08(q,J=32.3Hz);19F
NMR(376MHz,CDCl3)δ -78.39;EIMS m/z 224.5([M]+)。
1-(3,4-二溴苯基)-2,2,2-三氟乙醇
產物以澄清無色油狀物分離(5.92g,88%):1H NMR(400MHz,CDCl3)δ 7.76(d,J=2.0Hz,1H),7.66(d,J=8.3Hz,1H),7.29(dd,J=8.3,2.0Hz,1H),4.99(qd,J=6.4,4.2Hz,1H),2.75(d,J=4.3Hz,1H);13C NMR(101MHz,CDCl3)δ 134.52,133.81,132.60,127.45,126.19,125.16,123.71(q,J=283.8Hz).,71.57(q,J=32.5Hz);19F NMR(376MHz,CDCl3)δ -78.44;EIMS m/z 334([M]+)。
2,2,2-三氟-1-(3-(三氟甲氧基)苯基)乙醇
產物以澄清無色油狀物分離(20.9g,79%):1H NMR(400MHz,CDCl3)δ 7.55-7.36(m,3H),7.33-7.14(m,1H),5.06(m,1H),2.80(br m,1H);13C NMR(101MHz,CDCl3)δ 149.36(q,J=2.0Hz),136.04,129.99,125.78,123.91(q,J=282.8Hz),121.90,120.31(q,J=258.6Hz),120.12,72.04(q,J=32.3Hz);19F NMR(376MHz,CDCl3)δ -57.92,-78.49;EIMS m/z 260([M]+)。
2-氟-5-(2,2,2-三氟-1-羥乙基)苯甲腈
產物以澄清無色油狀物分離(5.47g,58%):1H NMR(400MHz,CDCl3)δ 7.80(dd,J=5.9,2.2Hz,1H),7.76(ddd,J=7.8,5.0,2.3Hz,1H),7.30(d,J=8.6Hz,1H),δ 5.09(qd,J=6.3,4.2Hz,1H),3.12(bm,1H);13C NMR(101MHz,CDCl3)δ 163.49(d,J=261.7Hz),134.23(d,J=8.6Hz),132.67,131.17,123.66(q,J=282.4Hz),116.79(d,J=20.1Hz),113.39,100.96(d,J=194.9),71.07(q,J=32.5Hz);19F NMR(376MHz,CDCl3)δ -78.70,-105.22;EIMS m/z 219([M]+)。
1-(3-溴-5-氯苯基)-2,2,2-三氟乙醇
產物以黃色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 7.78(s,1H),7.67(s,1H),7.57(s,1H),7.15(d,J=5.7Hz,1H);EIMS m/z 288([M]+);IR(薄膜)3435,1175,750cm-1。
1-(3-溴-5-氟苯基)-2,2,2-三氟乙醇
產物以淺黃色液體狀分離:1H NMR(400MHz,
CDCl3)δ 7.43(s,1H),7.29-7.26(m,1H),7.18(d,J=8.8Hz,1H),5.03-4.98(m,1H),3.60(bs,1H)。
;EIMS m/z 272.0([M]+);IR(薄膜)3400,1176,520cm-1。
1-(3,5-二氯苯基)-2,2,3,3,3-五氟丙-1-醇
使用五氟乙基三甲基矽烷,分離呈白色固體狀之產物(6.22g,88%):mp 71-73℃;1H NMR(400MHz,CDCl3)δ 7.42(t,J=1.9Hz,1H),7.37(d,J=1.8Hz,2H),5.11(dt,J=16.2,5.7Hz,1H),2.62(d,J=4.9Hz,1H);13C NMR(101MHz,CDCl3)δ 136.90,135.31,129.84,126.38,70.94(dd,J=28.2,23.1Hz);19F NMR(376MHz,CDCl3)δ -81.06,-120.94(d,J=277.5Hz),-129.18(d,J=277.5Hz);EIMS m/z 295([M]+)。
2,2,3,3,3-五氟-1-(3,4,5-三氯苯基)丙-1-醇
使用五氟乙基三甲基矽烷,分離呈灰白色半固體狀之產物:1H NMR(300MHz,DMSO-d 6)δ 7.78(s,2H),7.29(d,J=5.4Hz,),5.50-5.40(m,1H);EIMS m/z 328.0([M]+);IR(薄膜)3459,1188,797cm-1。
2,2,2-三氟-1-(3-(三氟甲基)苯基)乙醇
產物以淡黃色狀分離(13.8g,89%):1H NMR(400MHz,CDCl3)δ 7.77(s,1H),7.70-7.67(m,2H),7.55(t,J=7.8Hz,1H),5.12(q,J=6.6Hz,1H),2.76(s,1H);19F NMR(376MHz,CDCl3)δ -62.8,-78.5;EIMS m/z 244([M]+)。
1-(3,4-二氯-5-甲基苯基)-2,2,2-三氟乙醇
產物以淡淺黃色狀分離:1H NMR(400MHz,CDCl3)δ 7.44(s,1H),7.26(s,1H),4.98-4.95(m,1H),2.61(d,J=4.4Hz,1H),2.44(s,3H)。
;EIMS m/z 258.1([M]+);IR(薄膜)3421,2926,1129,748cm-1。
1-(3-氯-5-乙基苯基)-2,2,2-三氟乙醇
產物以灰棕色液體狀分離(0.43g,85%):1H NMR(300MHz,DMSO-d6)δ 7.34(s,1H),7.31-7.30(m,2H),6.99(d,J=5.7Hz,1H),5.23-5.16(m,1H),2.67(m,2H),
1.19(t,J=7.8Hz,3H);EIMS m/z 238.0([M]+);IR(薄膜)3361,1172,749cm-1。
1-(4-溴-3,5-二氯苯基)-2,2,2-三氟乙醇
產物以無色液體狀分離:1H NMR(300MHz,DMSO-d6)δ 7.75(s,2H),7.24(d,J=6.0Hz,1H),5.34-5.29(m,1H);EIMS m/z 321.88([M]+);IR(薄膜)3420,1706,1267,804,679cm-1。
1-(3,5-二溴-4-氯苯基)-2,2,2-三氟乙醇
產物以淺黃色膠狀物分離:1H NMR(300MHz,DMSO-d6)δ 7.89(s,2H),7.20(d,J=6.0Hz,1H)5.34-5.30(m,1H);EIMS m/z 366.0([M]+)。
步驟2. 1-(1-溴-2,2,2-三氟乙基)-3,5-二氯苯(AI1).向經攪拌之1-(3,5-二氯苯基)-2,2,2-三氟乙醇(4.0g,16.3mmol)於CH2Cl2(50mL)中之溶液中添加NBS(2.9g,16.3mmol)及亞磷酸三苯酯(5.06g,16.3mmol),且將所得反應混合物在回流下加熱18h。在利用TLC認為反應完全之後,將反應混合物冷卻至25℃且在減壓下濃縮。利用急驟管柱層析(SiO2,100-200篩目;用100%戊烷溶離)進行純化,得
到呈液體狀之標題化合物(2.0g,40%):1H NMR(400MHz,CDCl3)δ 7.41(s,3H),5.00(m,1H);EIMS m/z 306([M]+)。
以下化合物根據實例1之步驟2中揭示之程序製造。
5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(AI6)
產物以無色油狀物分離(300mg,60%):1H NMR(400MHz,CDCl3)δ 7.59(s,2H),5.00(m,1H);EIMS m/z 340.00([M]+)。
5-(1-溴-2,2,2-三氟乙基)-1,3-二氯-2-氟苯(AI7)
產物以無色油狀物分離(320mg,60%):1H NMR(400MHz,CDCl3)δ 7.45(s,2H),5.00(m,2H);EIMS m/z 324.00([M]+)。
4-(1-溴-2,2,2-三氟乙基)-1,2-二氯苯(AI8)
產物以無色油狀物分離(300mg,60%):1H NMR(400MHz,CDCl3)δ 7.63(s,1H),7.51(m,1H),7.35(m,1H),
5.01(m,1H);EIMS m/z 306.00([M]+)。
1,3-二溴-5-(1-溴-2,2,2-三氟乙基)苯
標題分子以無色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.71(s,1H),7.59(s,2H),5.04-4.97(m,1H);EIMS m/z 394.6([M]+);IR(薄膜)1114,535cm-1。
1-(1-溴-2,2,2-三氟乙基)-3-氟-5-(三氟甲基)苯
標題分子以無色液體狀分離:1H NMR(400MHz,DMSO-d 6)δ 7.90(d,J=8.4Hz,1H),7.79-7.77(m,2H),6.40-6.34(m,1H);EIMS m/z 324.00([M]+);IR(薄膜)1175,525cm-1。
1-(1-溴-2,2,2-三氟乙基)-3-氯-5-(三氟甲基)苯
標題分子以無色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.71(s,1H),7.67(s,1H),7.64(s,1H),5.15-5.09(m,1H);EIMS m/z 340.00([M]+);IR(薄膜)1178,750,540cm-1。
4-(1-溴-2,2,2-三氟乙基)-1-氟-2-(三氟甲基)苯
標題分子以無色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.75-7.72(m,2H),7.28-7.24(m,1H),5.19-5.16(m,1H);EIMS m/z 326.0([M]+);IR(薄膜)1114,571cm-1。
5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氟苯
標題分子以棕色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.23-7.12(m,2H),5.05-4.98(m,1H);EIMS m/z 292.0([M]+);IR(薄膜)1116,505cm-1。
1-(1-溴-2,2,2-三氟乙基)-2,3,4-三氟苯
標題分子以無色油狀物分離:1H NMR(300MHz,CDCl3)δ 7.44(qd,J=m,1H),7.11-7.03(m,1H),5.53-5.45(m,1H)。
1-(1-溴-2,2,2-三氟乙基)-2,4,5-三氯苯
標題分子以灰白色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 8.06(d,J=2.1Hz,1H),7.71(s,1H),6.45-6.37(m,1H);EIMS m/z 340.0([M]+);IR(薄膜)1186,764,576cm-1。
4-(1-溴-2,2,2-三氟乙基)-1-氯-2-硝基苯
標題分子以灰白色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 8.30(s,1H),7.92(d,J=9.0Hz,1H),6.43-6.35(m,1H);EIMS m/z 317.0([M]+);IR(薄膜)2927,1540,1353,1177,766,530cm-1。
5-(1-溴-2,2,2-三氟乙基)-2-氟-1,3-二甲基苯
標題分子以無色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 7.32(d,J=7.2Hz,2H),6.15-6.07(m,1H),3.23(s,6H);ESIMS m/z 284.1([M+H]+);IR(薄膜)2962,1112,500cm-1。
4-(1-溴-2,2,2-三氟乙基)-1-氟-2-甲基苯
標題分子以無色液體狀分離:1H NMR(300MHz,
CDCl3)δ 7.34-7.28(m,2H),7.04-6.98(m,1H),5.10-5.03(m,1H),2.29(s,3H);EIMS m/z 270.1([M]+);IR(薄膜)2989,1163cm-1。
1-(1-溴-2,2,3,3,3-五氟丙基)-3,5-二氯苯
標題分子以無色液體狀分離:1H NMR(400MHz,DMSO-d 6)δ 7.79(t,J=2.0Hz,1H),7.63(S,2H),6.37-6.29(m,1H);EIMS m/z 356([M]+);IR(薄膜)1673,1130,715,518cm-1。
4-(1-溴-2,2,2-三氟乙基)-2-氯-1-甲基苯
標題分子以無色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.55-7.50(m,2H),7.44(d,J=8.4Hz,1H),6.24-6.16(m,1H);IR(薄膜)2983,1112,749,564cm-1。
1,2-二溴-4-(1-溴-2,2,2-三氟乙基)苯
標題分子以無色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.75(s,1H),7.67(d,J=8.4Hz,1H),7.33-7.30(m,1H),5.07-5.00(m,1H);EIMS m/z 393.8([M]+);IR(薄膜)
2981,1644,1165cm-1。
1-(1-溴-2,2,2-三氟乙基)-3-(三氟甲氧基)苯
標題分子以無色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 7.65-7.60(m,2H),7.56-7.50(m,2H),6.35-6.27(m,1H);EIMS m/z 322([M]+);IR(薄膜)3413,1161,564cm-1。
5-(1-溴-2,2,2-三氟乙基)-2-氟苯甲腈
標題分子以淺黃色液體狀分離:1H NMR(300MHz,CDCl3)δ 8.15-8.12(m,1H),8.00-7.98(m,1H),7.69-7.63(m,1H),6.31-6.26(m,1H);EIMS m/z 280.9([M]+)。
1-溴-3-(1-溴-2,2,2-三氟乙基)-5-氯苯
標題分子以淺黃色液體狀分離:1H NMR(400MHz,DMSO-d 6)δ 7.90(s,1H),7.74(s,1H),7.65(s,1H),6.26-6.20(m,1H);EIMS m/z 349.9([M]+);IR(薄膜)1114,764cm-1。
1-溴-3-(1-溴-2,2,2-三氟乙基)-5-氟苯
標題分子以無色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.43(s,1H),7.32-7.29(m,1H),7.22(d,J=8.8Hz,1H),1.06(q,1H);EIMS m/z 334.0([M]+);IR(薄膜)3087,1168,533cm-1。
5-(1-溴-2,2,3,3,3-五氟丙基)-1,2,3-三氯苯
標題分子以無色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 7.85(s,2H),6.38-6.29(m,1H);EIMS m/z 389.9([M]+);IR(薄膜)1208,798,560cm-1。
4-(1-溴-2,2,2-三氟乙基)-2,6-二氟苯甲腈
標題分子以紫色固體狀分離:mp 59-63℃;1H NMR(400MHz,CDCl3)δ 7.25(s,2H),5.11-5.07(m,1H);ESIMS m/z 299.0([M+H]+)。
1-(1-溴-2,2,2-三氟乙基)-3-(三氟甲基)苯
標題分子以無色液體狀分離:mp 59-63℃;1H NMR(300MHz,CDCl3)δ 7.75-7.67(m,3H),7.57-7.52(m,1H),5.20-5.13(m,1H);ESIMS m/z 306.0([M]+);IR(薄膜)3436,2925,1265,749cm-1。
5-(1-溴-2,2,2-三氟乙基)-1,3-二氟-2-甲氧基苯
標題分子以淺黃色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.08(d,J=8.4Hz,2H),5.03-4.98(m,1H),4.04(s,3H);ESIMS m/z 304.1([M+H]+);IR(薄膜)1114,613cm-1。
5-(1-溴-2,2,2-三氟乙基)-1,2-二氯-3-甲基苯
標題分子以無色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.46(s,1H),7.27(s,1H),5.04-4.99(m,1H),2.44(s,3H);EIMS m/z 320.0([M]+);IR(薄膜)2925,1112,752,580cm-1。
4-(1-溴-2,2-二氟丙基)-1,2-二氯苯
標題分子以無色液體狀分離:1H NMR(300MHz,
DMSO-d6)δ 7.76-7.70(m,2H),7.54(dd,J=8.41.8Hz,1H),5.81-5.73(m,1H),1.67(d,J=18.9Hz,3H);EIMS m/z 304.0([M]+);IR(薄膜)1118,800,499cm-1。
1-(1-溴-2,2,2-三氟乙基)-3-氯-5-乙基苯
標題分子以無色液體狀分離:1H NMR(400MHz,DMSO-d6)δ 7.43(d,J=5.6Hz,2H),7.39(s,1H),6.20-6.16(m,1H),2.68-2.62(m,2H),1.19(t,J=7.6Hz,3H);EIMS m/z 300.0([M]+);IR(薄膜)2970,1167,716,539cm-1。
2-溴-5-(1-溴-2,2,2-三氟乙基)-1,3-二氯苯
標題分子以無色液體狀分離:1H NMR(400MHz,DMSO-d6)δ 7.79(s,2H),6.27-6.21(m,1H);EIMS m/z 383.9([M]+);IR(薄膜)2924,1114,749,534cm-1。
1,3-二溴-5-(1-溴-2,2,2-三氟乙基)-2-氯苯
標題分子以淺黃色液體狀分離:1H NMR(300MHz,DMSO-d6)δ 7.97(s,2H),6.27-6.19(m,1H);EIMS
m/z 428.0([M]+)。
步驟1. 4-乙烯基苯甲醯氯(AI10). 在0℃下經15分鐘(min)之時間向經攪拌之4-乙烯基苯甲酸(1g,6.75mmol)於CH2Cl2(20mL)中之溶液中逐滴添加催化量之DMF及乙二醯氯(1.27g,10.12mmol)。在25℃下攪拌反應混合物6h。在利用TLC認為反應完全之後,在減壓下濃縮反應混合物,得到粗酸氯化物。
步驟2. N-甲基-4-乙烯基苯甲醯胺(AI9). 在0℃下向含1M N-甲胺之THF(13.5mL,13.5mmol)中添加TEA(1.34mL,10.12mmol)及含來自上文步驟1之酸氯化物之THF(10mL),且在25℃下攪拌反應混合物3h。在利用TLC認為反應完全之後,反應混合物用水淬滅且接著用EtOAc萃取(3×)。合併之EtOAc層用鹽水洗滌且經Na2SO4乾燥且在減壓下濃縮,得到呈灰白色固體狀之標題化合物(650mg,60%):1H NMR(400MHz,CDCl3)δ 7.76(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),6.79(m,1H),6.20(br s,1H),5.82(d,J=17.6Hz,1H),5.39(d,J=10.8Hz,1H);ESIMS m/z 161.95([M+H]+)。
以下化合物根據實例2中揭示之程序製造。
N,N-二甲基-4-乙烯基苯甲醯胺(AI11)
產物以灰白色固體狀分離(650mg,60%):1H NMR(400MHz,CDCl3)δ 7.42(m,4H),6.71(m,1H),580(d,J=17.6Hz,1H),5.31(d,J=10.8Hz,1H),3.05(s,3H),3.00(s,3H);ESIMS m/z 176.01([M+H]+)。
N-(2,2,3-三氟甲基)-4-乙烯基苯甲醯胺(AI12)
產物以灰白色固體狀分離(900mg,60%):1H NMR(400MHz,CDCl3)δ 7.76(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),6.79(m,1H),6.20(br s,1H),5.82(d,J=17.6Hz,1H),5.39(d,J=10.8Hz,1H),4.19(m,2H);ESIMS m/z 230.06([M+H]+)。
N-嗎啉基(4-乙烯基苯基)甲酮(AI13)
產物以白色固體狀分離(850mg,60%):ESIMS m/z 218.12([M+H]+)。
步驟1. 4-甲醯基-2-甲基苯甲酸(AI15). 在-78℃下向經攪拌之4-溴-2-甲基苯甲酸(10g,46.4mmol)於無水
THF(360mL)中之溶液中添加n-BuLi(1.6M己烷溶液;58.17mL,93.0mmol)及DMF(8mL)。將反應混合物在-78℃下攪拌1h,接著溫至25℃且攪拌1h。反應混合物用1N HCl溶液淬滅且用EtOAc萃取。合併之EtOAc萃取物用鹽水洗滌且經Na2SO4乾燥且在減壓下濃縮。用正己烷洗滌殘餘物,得到呈固體狀之標題化合物(3.0g,40%):mp 196-198℃;1H NMR(400MHz,DMSO-d 6)δ 13.32(br s,1H),10.05(s,1H),7.98(m,1H),7.84(m,2H),2.61(s,3H);ESIMS m/z 163.00([M-H]-)。
步驟2. 4-甲醯基-2-甲基苯甲酸乙酯(AI16). 向經攪拌之4-甲醯基-2-甲基苯甲酸(3g,18.2mmol)於EtOH(30mL)中之溶液中添加H2SO4,且將反應混合物在80℃下加熱18h。將反應混合物冷卻至25℃且在減壓下濃縮。殘餘物用EtOAc稀釋且用水洗滌。合併之EtOAc萃取物用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈固體狀之標題化合物(2.8g,80%):1H NMR(400MHz,CDCl3)δ 10.05(s,1H),8.04(m,1H),7.75(m,2H),4.43(m,2H),2.65(s,3H),1.42(m,3H)。
步驟3. 2-甲基-4-乙烯基苯甲酸乙酯(AI14). 在25℃下向經攪拌之4-甲醯基-2-甲基苯甲酸乙酯(2.8g,4mmol)於1,4-二噁烷(20mL)中之溶液中添加K2CO3(3.01g,21.87mmol)及溴化甲基三苯基鏻(7.8g,21.87mmol)。接著將反應混合物在100℃下加熱18h。在利用TLC認為反應完全之後,將反應混合物冷卻至25℃且過濾,且在減壓下
濃縮濾液。粗化合物藉由急驟層析(SiO2,100-200篩目;用25-30%配於正己烷之EtOAc溶離)純化,得到呈固體狀之標題化合物(2.0g,72%):1H NMR(400MHz,CDCl3)δ 7.86(m,1H),7.27(m,2H),6.68(dd,J=17.6,10.8Hz,1H),5.84(d,J=17.6Hz,1H),5.39(d,J=10.8Hz,1H),4.39(m,2H),2.60(s,3H),1.40(m,3H);ESIMS m/z 191.10([M-H]-);IR(薄膜)2980,1716,1257cm-1。
步驟1. 4-溴-2-氯苯甲酸第三丁酯(AI18). 向經攪拌之4-溴-2-氯苯甲酸(5g,21.37mmol)於THF(30mL)中之溶液中添加二碳酸二第三丁酯(25.5g,25.58mmol)、TEA(3.2g,31.98mmol)及DMAP(0.78g,6.398mmol),且將反應混合物在25℃下攪拌18h。反應混合物用EtOAc稀釋且用水洗滌。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。殘餘物藉由急驟層析(SiO2,100-200篩目;用配於正己烷之2-3% EtOAc溶離)純化,得到呈液體狀之標題化合物(3.2g,51%):1H NMR(400MHz,CDCl3)δ 7.62(m,2H),7.44(d,J=8.4Hz,1H),1.59(s,9H);ESIMS m/z 290.10([M+H]+);IR(薄膜)1728cm-1。
以下化合物根據實例4之步驟1中揭示之程序製造。
2-溴-4-碘苯甲酸第三丁酯(AI19)
產物以無色油狀物分離(1.2g,50%):1H NMR(400MHz,CDCl3)δ 8.01(s,1H),7.68(d,J=8.4Hz,1H),7.41(d,J=8.0Hz,1H),1.59(s,9H);ESIMS m/z 382.10([M+H]+);IR(薄膜)1727cm-1。
4-溴-2-(三氟甲基)苯甲酸第三丁酯(AI20)
產物以無色油狀物分離(1g,52%):1H NMR(400MHz,CDCl3)δ 7.85(s,1H),7.73(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),1.57(s,9H);ESIMS m/z 324.10([M+H]+);IR(薄膜)1725cm-1。
步驟2. 2-氯-4-乙烯基苯甲酸第三丁酯(AI17).向經攪拌之4-溴-2-氯苯甲酸第三丁酯(1.6g,5.50mmol)於甲苯(20mL)中之溶液中添加Pd(PPh3)4(0.31mg,0.27mmol)、K2CO3(2.27g,16.5mmol)及乙烯基酸酐吡啶複合物(2.0g,8.3mmol),且將反應混合物加熱至回流後持續16h。將反應混合物過濾,且濾液用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;用配於正己烷之5-6% EtOAc溶離)進行純化,得到呈液體狀之標題化合物(0.6g,46%):1H NMR(400MHz,CDCl3)δ 7.72(d,J=8.1Hz,1H),7.44(m,1H),7.31(d,J=8.0Hz,1H),6.69(dd,J=17.6,10.8Hz,1H),5.85(d,J
=17.6Hz,1H),5.40(d,J=10.8Hz,1H),1.60(s,9H);ESIMS m/z 238.95([M+H]+);IR(薄膜)2931,1725,1134cm-1。
以下化合物根據實例4之步驟2中揭示之程序製造。
2-溴-4-乙烯基苯甲酸第三丁酯(AI21)
產物以無色油狀物分離(1g,52%):1H NMR(400MHz,CDCl3)δ 7.68(m,2H),7.36(d,J=8.0Hz,1H),6.68(dd,J=17.6,10.8Hz,1H),5.84(d,J=17.6Hz,1H),5.39(d,J=10.8Hz,1H),1.60(s,9H);ESIMS m/z 282.10([M+H]+);IR(薄膜)2978,1724,1130cm-1。
2-(三氟甲基)-4-乙烯基苯甲酸第三丁酯(AI22)
產物以無色油狀物分離(1.2g,50%):1H NMR(400MHz,CDCl3)δ 7.71(d,J=6.4Hz,2H),7.59(d,J=7.6Hz,1H),6.77(dd,J=17.6,10.8Hz,1H),5.89(d,J=17.6Hz,1H),5.44(d,J=10.8Hz,1H),1.58(s,9H);ESIMS m/z 272.20([M+H]+);IR(薄膜)2982,1727,1159cm-1。
向經攪拌之2-溴-4-乙烯基苯甲酸第三丁酯(0.5g,1.77mmol)於DMF(20mL)中之溶液中添加CuCN(0.23g,2.65mmol),且將反應混合物在140℃下加熱3h。將反應混合物冷卻至25℃,用水稀釋,且用EtOAc萃取。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。殘餘物藉由急驟層析(SiO2,100-200篩目;用配於正己烷之15% EtOAc溶離)純化,得到呈白色固體狀之標題化合物(0.3g,72%):mp 51-53℃;1H NMR(400MHz,CDCl3)δ 8.03(s,1H),7.77(s,1H),7.64(d,J=8.4Hz,1H),6.75(dd,J=17.6,10.8Hz,1H),5.93(d,J=17.6Hz,1H),5.51(d,J=10.8Hz,1H),1.65(s,9H);ESIMS m/z 229.84([M+H]+);IR(薄膜)2370,1709,1142cm-1。
向經攪拌之4-碘-2-溴苯甲酸(5g,15.29mmol)於EtOH(100mL)中之溶液中添加H2SO4(5mL),且將反應混合物在80℃下加熱18h。將反應混合物冷卻至25℃且在減壓下濃縮。殘餘物用EtOAc(2×100mL)稀釋且用水(100mL)洗滌。合併之EtOAc萃取物用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈淺黃色固體狀之化合物(5g,92%):1H NMR(400MHz,DMSO-d 6)δ 8.04(d,J=1.2Hz,1H),7.71(d,J=7.6Hz,1H),7.51(d,J=8.4Hz,1H),4.41(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H)。
以下化合物根據實例6中揭示之程序製造。
4-溴-2-氯苯甲酸乙酯(AI47)
標題化合物以灰白色固體狀分離(2.0g,80%):1H NMR(400MHz,DMSO-d 6)δ 8.25(d,J=1.2Hz,1H),7.79(d,J=7.6Hz,1H),7.65(d,J=8.4Hz,1H),4.65(q,J=7.2Hz,2H),1.56(t,J=7.2Hz,3H)。
4-溴-2-甲基苯甲酸乙酯(AI48)
標題化合物以淺黃色液體狀分離(3.0g,83%):1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.4Hz,1H),7.41(s,1H),7.39(d,J=8.4Hz,1H),4.42(q,J=7.2Hz,2H),2.60(s,3H),1.40(t,J=7.2Hz,3H)ESIMS m/z 229.11([M+H]+);IR(薄膜)1725cm-1。
4-溴-2-氟苯甲酸乙酯(AI49)
標題化合物以無色液體狀分離(9.0g,79%):1H NMR(400MHz,DMSO-d 6)δ 7.84(t,J=8.4Hz,1H),7.76(d,
J=2.0Hz,1H),7.58(d,J=1.6Hz,1H),4.34(q,J=7.2Hz,2H),1.32(t,J=7.2Hz,3H);ESIMS m/z 246.99([M+H]+),IR(薄膜)1734cm-1。
在0℃下向經攪拌之4-溴-2-氟苯甲酸(2.0g,9.17mmol)於THF(16mL)中之溶液中逐滴添加含1.0M溴化乙基鎂之THF(32mL,32.0mmol),且將所得反應混合物在環境溫度下攪拌18h。反應混合物用2N HCl淬滅且用EtOAc萃取。合併之EtOAc層經無水Na2SO4乾燥且在減壓下濃縮,得到呈無色液體狀之粗4-溴-2-乙基苯甲酸(0.4g),其未經純化即用於下一步驟:1H NMR(400MHz,CDCl3)δ 7.64(d,J=8.4Hz,1H),7.47(m,1H),7.43(m,1H),2.95(q,J=4.0Hz,2H),1.32(t,J=4.0Hz,3H);ESIMS m/z 228.97([M+H]+)。
標題化合物根據實例6中之程序由4-溴-2-乙基苯甲酸合成,以無色液體狀分離(0.15g,68%):1H NMR(400MHz,DMSO-d 6)δ 7.90(d,J=8.4Hz,1H),7.47(m,2H),4.40(q,J=7.2Hz,2H),3.06(q,J=7.6Hz,2H),1.42(t,J=7.2Hz,3H),1.26(t,J=7.6Hz,3H);ESIMS m/z 226.96([M-H]-);IR(薄膜)3443,1686,568cm-1。
向經攪拌之2-溴-4-碘苯甲酸乙酯(5g,14.3mmol)於THF/水(100mL,9:1)中之溶液中添加乙烯基三氟硼酸鉀(1.89g,14.3mmol)、Cs2CO3(18.27g,56.07mmol)及三苯基膦(0.22g,0.85mmol),且反應混合物用氬氣脫氣20min,接著以PdCl2(0.05g,0.28mmol)饋入。將反應混合物加熱至回流後持續16h。將反應混合物冷卻至環境溫度,且經由Celite®床過濾且用EtOAc洗滌。再用EtOAc萃取濾液,且合併之有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物藉由管柱層析(SiO2,100-200篩目;用配於石油醚之2% EtOAc溶離)純化,得到呈淡棕色膠狀物質之標題化合物(2g,56%):1H NMR(400MHz,CDCl3)δ 7.78(d,J=8.4Hz,1H),7.71(d,J=1.2Hz,1H),7.51(d,J=8.4Hz,1H),6.69(dd,J=17.6,10.8Hz,1H),5.86(d,J=17.6Hz,1H),5.42(d,J=11.2Hz,1H),4.42(q,J=7.2Hz,2H),1.43(t,J=3.6Hz,3H);ESIMS m/z 255.18([M+H]+);IR(薄膜)1729cm-1。
以下化合物根據實例8中揭示之程序製造。
2-甲基-4-乙烯基苯甲酸乙酯(AI52)
標題化合物以無色液體狀分離(0.8g,80%):1H NMR(400MHz,CDCl3)δ 7.89(d,J=8.4Hz,1H),7.27(m,
2H),6.79(dd,J=17.6,10.8Hz,1H),5.86(d,J=17.6Hz,1H),5.42(d,J=11.2Hz,1H),4.42(q,J=7.2Hz,2H),2.60(s,3H),1.43(t,J=7.2Hz,3H);ESIMS m/z 191.10([M+H]+);IR(薄膜)1717,1257cm-1。
2-氟-4-乙烯基苯甲酸乙酯(AI53)
標題化合物以淺黃色液體狀分離(2.0g,50%):1H NMR(400MHz,DMSO-d 6)δ 7.87(t,J=8.0Hz,1H),7.51(d,J=16.0Hz,1H),7.48(d,J=16.0Hz,1H),6.82(dd,J=17.6,10.8Hz,1H),6.09(d,J=17.6Hz,1H),5.50(d,J=10.8Hz,1H),4.35(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H);ESIMS m/z 195.19([M+H]+);IR(薄膜)1728cm-1。
向經攪拌之2-氯-4-溴苯甲酸乙酯(2g,7.63mmol)於DMSO(20mL)中之溶液中添加乙烯基三氟硼酸鉀(3.06g,22.9mmol)及K2CO3(3.16g,22.9mmol)。反應混合物用氬氣脫氣30min。添加二氯化雙三苯基膦(二苯基膦基二茂鐵)鈀(0.27g,0.38mmol),且將反應混合物加熱至80℃後持續1h。反應混合物用(100mL)水稀釋,用EtOAc(2×50mL)萃取,用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,獲得呈棕色膠狀物質之化合物(1.1g,69%):1H NMR(400MHz,
CDCl3)δ 7.81(d,J=8.4Hz,1H),7.46(s,1H),7.33(d,J=8.4Hz,1H),6.70(dd,J=17.6,11.2Hz,1H),5.87(d,J=17.6Hz,1H),5.42(d,J=10.8Hz,1H),4.41(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H);ESIMS m/z 211.22([M+H]+);IR(薄膜)1729,886cm-1。
以下化合物根據實例9中揭示之程序製造。
2-乙基-4-乙烯基苯甲酸乙酯(AI55)
標題化合物以無色液體狀分離(1.0g,66%):1H NMR(300MHz,CDCl3)δ 7.85(m,1H),7.29(m,2H),6.76(d,J=10.8Hz,1H),5.86(d,J=17.6Hz,1H),5.36(d,J=10.5Hz,1H),4.41(q,J=7.2Hz,2H),3.10(q,J=7.2Hz,2H),1.40(t,J=7.2Hz,3H),1.30(t,J=7.2Hz,3H);ESIMS m/z 205.26([M+H]+);IR(薄膜)1720,1607,1263cm-1。
2-甲氧基-4-乙烯基苯甲酸甲酯(AI56)
標題化合物以淺黃色液體狀分離(1.2g,75%):1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.0Hz,1H),7.04(d,J=1.2Hz,1H),6.97(s,1H),6.74(dd,J=11.2,11.2Hz,1H),5.86(d,J=17.6Hz,1H),5.39(d,J=17.6Hz,1H)3.93(s,3H),3.91(s,3H);ESIMS m/z 193.18([M+H]+);IR(薄膜)
1732cm-1。
2-(甲基硫基)-4-乙烯基苯甲酸乙酯
標題化合物以棕色液體狀分離:1H NMR(300MHz,CDCl3)δ 7.98(d,J=8.4Hz,1H),7.23-7.18(m,2H),6.78(dd,J=17.7,10.8,Hz,1H),5.89(d,J=17.4Hz,1H),5.42(d,J=10.8Hz,1H),4.39-4.36(m,2H),2.48(s,3H),1.39(t,J=6.9Hz,3H);ESIMS m/z 221.9([M+H]+);IR(薄膜)1708cm-1。
向經攪拌之2-甲基-4-乙烯基苯甲酸乙酯(2.0g,10.5mmol)於1,2-二氯苯(25mL)中之溶液中添加1-(1-溴-2,2,2-三氟乙基)-3,5-二氯苯(6.44g,21.0mmol)、CuCl(208mg,21mmol)及2,2-聯吡啶(0.65g,4.1mmol)。反應混合物用氬氣脫氣30min且接著在180℃下攪拌24h。在利用TLC認為反應完全之後,將反應混合物冷卻至25℃且過濾,且在減壓下濃縮濾液。藉由急驟層析(SiO2,100-200篩目;用配於石油醚之25-30% EtOAc溶離)進行純化,得到
呈固體狀之標題化合物(1.7g,40%):1H NMR(400MHz,CDCl3)δ 7.91(d,J=8.0Hz,1H),7.37(m,1H),7.27-7.24(m,4H),6.59(d,J=16.0Hz,1H),6.59(dd,J=16.0,8.0Hz,1H),4.38(q,J=7.2Hz,2H),4.08(m,1H),2.62(s,3H),1.42(t,J=7.2Hz,3H);ESIMS m/z 415.06([M-H]-);IR(薄膜)1717,1255,1114cm-1。
化合物AI25、AI57-AI68及AC1-AC5(表1)根據實例10中揭示之程序製造。
(E)-乙基4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)-苯甲酸乙酯(AI25)
產物以淺棕色膠狀液體狀分離(500mg,40%):1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.0Hz,1H),7.71(m,1H),7.61(d,J=7.6Hz,1H),7.42(s,2H),6.70(d,J=16.0Hz,1H),6.57(dd,J=16.0,8.0Hz,1H),4.42(q,J=7.2Hz,2H),4.19(m,1H),1.40(t,J=7.6Hz,3H);ESIMS m/z 502.99([M-H]-);IR(薄膜)1730,1201,1120,749cm-1。
(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-氟苯甲酸乙酯(AI57)
1H NMR(400MHz,CDCl3)δ 7.38(s,1H),7.26(s,3H),7.21(d,J=8.4Hz,1H),7.16(d,J=11.6Hz,1H),6.59(d,J=16.0Hz,1H),6.47(dd,J=,16.0,8.0Hz,1H),4.41(q,J=6.8Hz,2H),4.18(m,1H),1.41(t,J=6.8Hz,3H);ESIMS m/z 419.33([M-H]-);IR(薄膜)1723,1115,802cm-1。
(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-溴苯甲酸乙酯(AI58)
1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.0Hz,1H),7.67(s,1H),7.38(m,2H),7.26(m,2H),6.56(d,J=16.0Hz,1H),6.45(dd,J=16.0,7.6Hz,1H),4.42(q,J=7.2Hz,2H),4.39(m,1H),1.42(t,J=7.2Hz,3H);ESIMS m/z 481.22([M-H]-);IR(薄膜)1727,1114,801,685cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸乙酯(AI59)
1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.0Hz,1H),7.67(d,J=1.6Hz,1H),7.40(s,2H),7.36(d,J=1.6Hz,1H),6.56(d,J=16.0Hz,1H),6.44(dd,J=16.0,7.6Hz,1H),4.42(q,J=6.8Hz,2H),4.15(m,1H),1.42(t,J=6.8Hz,
3H);ESIMS m/z 514.74([M-H]-);IR(薄膜)1726,1115,808,620cm-1。
(E)-2-甲基-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸乙酯(AI60)
標題化合物以淡棕色膠狀物質分離:1H NMR(400MHz,CDCl3)δ 7.90(d,J=8.8Hz,1H),7.34(d,J=6.0Hz,2H),7.25(d,J=7.2Hz,2H),6.59(d,J=16.0Hz,1H),6.42(dd,J=16.0,8.0Hz,1H),4.38(q,J=7.2Hz,2H),4.19(m,1H),2.63(s,3H),1.41(t,J=7.2Hz,3H)。
(E)-2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸乙酯(AI61)
1H NMR(400MHz,CDCl3)δ 7.87(d,J=8.0Hz,1H),7.46(d,J=1.6Hz,1H),7.40(s,2H),7.31(d,J=1.6Hz,1H),6.57(d,J=16.0Hz,1H),6.44(dd,J=16.0Hz,,8.0Hz,1H),4.42(q,J=6.8Hz,2H),4.15(m,1H),1.42(t,J=6.8Hz,3H);ESIMS m/z 470.73([M-H]-);IR(薄膜)1726,1115,809,3072cm-1。
(E)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三
氟甲基)苯甲酸乙酯(AI62)
標題化合物以淺棕色液體狀分離(1.0g,46.3%):1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.0Hz,1H),7.71(s,1H),7.61(d,J=7.6Hz,1H),7.41(s,2H)6.65(d,J=16.0Hz,1H),6.49(dd,J=16.0,8.0Hz,1H),4.42(q,J=7.6Hz,2H),4.15(m,1H),1.42(t,J=7.6Hz,3H);ESIMS m/z 502.99([M-H]-);IR(薄膜)1730,1202,1120,750cm-1。
(E)-2-氯-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸乙酯(AI63)
1H NMR(400MHz,CDCl3)δ 7.85(d,J=6.0Hz,1H),7.46(d,J=1.8Hz,2H),7.34(m,1H),7.24(m,1H),6.57(d,J=16.2Hz,1H),6.45(dd,J=16.2,7.2Hz,1H),4.43(q,J=7.2Hz,2H),4.13(m,1H),1.41(t,J=7.2Hz,3H);ESIMS m/z 455.0([M+H]+);IR(薄膜)1728,1115,817cm-1。
(E)-2-氟-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸乙酯(AI64)
1H NMR(400MHz,CDCl3)δ 7.93(t,J=7.6Hz,1H),7.34(d,J=5.6Hz,2H),7.21(d,J=8.0Hz,1H),7.16(d,J=11.6Hz,1H),6.59(d,J=16.0Hz,1H),6.49(dd,J=16.0,7.6Hz,1H),4.42(q,J=7.6Hz,2H),4.13(m,1H),1.41(t,J=7.6Hz,3H);ESIMS m/z 436.81([M-H]-);IR(薄膜)1725cm-1。
(E)-2-溴-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸乙酯(AI65)
1H NMR(400MHz,CDCl3)δ 7.94(d,J=8.0Hz,1H),7.67(s,1H),7.36(m,3H),6.56(d,J=15.6Hz,1H),6.44(dd,J=15.6,8.0Hz,1H),4.42(q,J=6.8Hz,2H),4.10(m,1H),1.42(t,J=6.8Hz,3H);ESIMS m/z 498.74([M-H]-);IR(薄膜)1726,1114,820,623cm-1。
(E)-2-甲基-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸乙酯(AI66)
標題化合物以棕色半固體狀分離:1H NMR(400MHz,CDCl3)δ 7.90(d,J=8.8Hz,1H),7.34(d,J=6.0Hz,2H),7.25(d,J=7.2Hz,2H),6.59(d,J=16.0Hz,1H),6.42(dd,J=16.0Hz,8.0Hz,1H),4.38(q,J=7.2Hz,2H),4.19(m,1H),2.63(s,3H),1.41(t,J=7.2Hz,3H);ESIMS m/z 432.90([M-H]-);IR(薄膜)1715cm-1。
(E)-2-甲氧基-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸甲酯(AI67)
1H NMR(400MHz,CDCl3)δ 7.80(d,J=8.4Hz,1H),7.35(d,J=6.0Hz,2H),7.03(d,J=1.2Hz,1H),6.92(s,1H),6.59(d,J=15.6Hz,1H),6.42(dd,J=15.6,8.0Hz,1H),4.13(m,1H),3.93(s,3H),3.88(s,3H);ESIMS m/z 437.29([M+H]+);IR(薄膜)1724cm-1。
(E)-2-乙基-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸乙酯(AI68)
1H NMR(400MHz,CDCl3)δ 7.85(d,J=8.0Hz,1H),7.35(d,J=9.6Hz,2H),7.26(m,1H),7.24(m,1H),6.60(d,J=15.6Hz,1H),6.42(dd,J=15.6,8.0Hz,1H),
4.38(q,J=7.2Hz,2H),4.14(m,1H),3.01(q,J=7.6Hz 2H),1.41(t,J=7.2Hz,3H),1.26(t,J=7.6Hz,3H);ESIMS m/z 447.05([M-H]-);IR(薄膜)1715,1115,817cm-1。
(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(甲基硫基)苯甲酸乙酯
以棕色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.99(d,J=8.1Hz,2H),7.35-7.32(m,2H),7.21-7.16(m,2H),6.63(d,J=15.8Hz,1H),6.45(dd,J=15.9,7.8Hz,1H),4.41-4.31(m,2H),4.30-4.10(m,1H),2.47(s,3H),1.40(t,J=7.5Hz,3H);ESIMS m/z 466.88([M+H]+);IR(薄膜)1705,1114cm-1。
(E)-2-溴-4-(3-(3,5-二氟-4-甲氧基苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸乙酯
產物以淺黃色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.78(d,J=8.0Hz,1H),7.66(d,J=1.6Hz,1H),7.35-7.33(m,1H),6.96-6.90(m,2H),6.54(d,J=15.6Hz,1H),6.43(dd,J=15.6,8.0Hz,1H),4.39(q,J=6.8Hz,2H),4.09-4.05(m,1H),4.02(s,3H),1.40(t,J=7.2Hz,3H);
EIMS m/z 478.2([M]+);IR(薄膜)1727,1113cm-1。
向經攪拌之(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲酸乙酯(1.7g,4.0mmol)於1,4-二噁烷(10mL)中之溶液中添加11N HCl(30mL),且將反應混合物在100℃下加熱48h。將反應混合物冷卻至25℃且在減壓下濃縮。殘餘物用水稀釋且用氯仿(CHCl3)萃取。合併之有機層經Na2SO4乾燥且在減壓下濃縮,且粗化合物用正己烷洗滌,得到呈白色固體狀之標題化合物(0.7g,50%):mp 142-143℃;1H NMR(400MHz,DMSO-d 6)δ 12.62(br s,1H),7.81(d,J=8.0Hz,1H),7.66(s,3H),7.52-7.44(m,2H),6.89(dd,J=16.0,8.0Hz,1H),6.78-6.74(d,J=16.0Hz,1H),4.84(m,1H),2.50(s,3H);ESIMS m/z 387.05([M-H]-);IR(薄膜)3448,1701,1109,777cm-1。
以下化合物根據實例11中揭示之程序製造。
(E)-2-甲基-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(AI26)
產物以淺棕色膠狀液體狀分離(1g,46%):1H NMR(400MHz,CDCl3)δ 7.97(d,J=8.0Hz,1H),7.77(s,1H),7.65(m,1H),7.41(s,2H),6.68(d,J=16.0Hz,1H),6.53(dd,J=16.0,8.0Hz,1H),4.16(m,1H),2.50(s,3H);ESIMS m/z 422.67([M-H]-)。
(E)-2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(AI27)
產物以灰白色半固體狀分離(1g,45%):1H NMR(400MHz,CDCl3)δ 7.99(d,J=8.4Hz,1H),7.50(m,1H),7.40(s,1H),7.36(m,2H),6.59(d,J=15.6Hz,1H),6.48(dd,J=15.6,7.6Hz,1H),4.14(m,1H);ESIMS m/z 442.72([M-H]-);IR(薄膜)3472,1704,1113,808cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(AI28)
產物以棕色固體狀分離(1g,45%):mp 70-71℃;1H NMR(400MHz,CDCl3)δ 7.99(d,J=8.0Hz,1H),7.72(s,1H),7.40(m,3H),6.58(d,J=16.0Hz,1H),6.48(dd,J=16.0,8.0Hz,1H),4.14(m,1H);ESIMS m/z 484.75
([M-H]-);IR(薄膜)3468,1700cm-1。
(E)-2-氰基-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(AI29)
產物以灰白色固體狀分離(500mg,45%):mp 100-101℃;1H NMR(400MHz,CDCl3)δ 7.90(s,1H),7.85(d,J=7.6Hz,1H),7.72(d,J=8.0Hz,1H),7.65(br s,1H),7.42(s,2H),6.73(d,J=16.0Hz,1H),6.58(dd,J=16.0,8.0Hz,1H),4.19(m,1H);ESIMS m/z 431.93([M-H]-)。
(E)-4-(3-(3,4-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲酸(AI30)
產物以淺棕色液體狀分離(500mg,46%):1H NMR(400MHz,CDCl3)δ 8.03(m,1H),7.49(m,2H),7.29(m,1H),7.22(m,2H),6.73(d,J=16.0Hz,1H),6.58(dd,J=16.0,7.8Hz,1H),4.16(m,1H),2.64(s,3H);ESIMS m/z 386.84([M-H]-);IR(薄膜)3428,1690,1113,780cm-1。
(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲酸(AI31)
產物以白色固體狀分離(500mg,50%):mp 91-93℃;1H NMR(400MHz,CDCl3)δ 8.02(d,J=8.0Hz,1H),7.35(d,J=5.6Hz,1H),7.30(m,3H),6.61(d,J=16.0Hz,1H),6.48(dd,J=16.0,8.0Hz,1H),4.13(m,1H),2.65(s,3H);ESIMS m/z 406.87([M-H]-)。
(E)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)苯甲酸(AI33)
產物以白色固體狀分離(500mg,45%):mp 142-143℃;1H NMR(400MHz,CDCl3)δ 7.97(d,J=8.0Hz,1H),7.77(s,1H),7.65(m,1H),7.41(s,2H),6.68(d,J=16.0Hz,1H),6.53(dd,J=16.0,8.0Hz,1H),4.16(m,1H);ESIMS m/z 474.87([M-H]-)。
(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(AI69)
標題化合物以棕色固體狀分離(0.8g,28%):1H
NMR(400MHz,CDCl3)δ 13.42(br,1H),7.98(d,J=1.5Hz,1H),7.94(m,2H),7.75(d,J=8.1Hz,1H),7.65(m,1H),7.06(dd,J=15.9,9.0Hz,1H),6.80(d,J=15.9Hz,1H),4.91(m,1H);ESIMS m/z 484.75([M-H]-);IR(薄膜)3469,1700cm-1。
(E)-2-溴-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸(AI70)
標題化合物以黃色液體狀分離(0.3g,粗物質):1H NMR(300MHz,CDCl3)δ 7.79(d,J=8.1Hz,1H),7.67(s,1H),7.34(m,3H),6.56(d,J=15.9Hz,1H),6.45(dd,J=15.9,7.6Hz,1H),4.43(m,1H);ESIMS m/z 471.0([M-H]-)。
(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-乙基苯甲酸(AI71)
標題化合物以棕色膠狀物質分離(0.2g,粗物質):1H NMR(300MHz,DMSO-d 6)δ 12.5(br,1H),7.85(d,J=6.3Hz,2H),7.75(d,J=8.1Hz,1H),7.52(m,2H),6.96(dd,J=8.7,8.7Hz,1H),6.78(d,J=15.6Hz,1H),4.80(m,1H),4.06(q,J=7.2Hz,2H),1.33(t,J=7.2Hz,3H);ESIMS
m/z 419.06([M-H]-)。
(E)-2-氯-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸(AI72)
標題化合物以黃色液體狀分離(0.7g,95%):1H NMR(300MHz,CDCl3)δ 7.85(d,J=6.0Hz,1H),7.46(d,J=1.8Hz,1H),7.41(s,3H),6.57(d,J=16.0Hz,1H),6.45(dd,J=16.0,8.0Hz,1H),4.16(m,1H);ESIMS m/z 455.0([M+H]+);IR(薄膜)1728,1115,817cm-1。
(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲酸(AI73)
標題化合物以淡棕色膠狀物質分離(0.7g,38%):mp 91-93℃;1H NMR(400MHz,CDCl3)δ 8.02(d,J=8.0Hz,1H),7.35(d,J=5.6Hz,1H),7.30(m,3H),6.10(d,J=16.0Hz,1H),6.46(dd,J=16.0,8.0Hz,1H),4.03(m,1H),2.65(s,3H);ESIMS m/z 406.87([M-H]-)。
(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-氟苯甲酸(AI74)
標題化合物以淡棕色液體狀分離(0.3g,粗物質):ESIMS m/z 393.15([M-H]-)。
(E)-2-溴-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)苯甲酸(AI75)
標題化合物以淡棕色液體狀分離(0.35g,粗物質):ESIMS m/z 451.91([M-H]-)。
(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(甲基硫基)苯甲酸
1H NMR(400MHz,CDCl3)δ 7.88-7.85(m,3H),7.46(d,J=6.8Hz,1H),7.37(s,1H),6.99(dd,J=15.6,8.8Hz,1H),6.85(d,J=16.0Hz,1H),4.85-4.81(m,2H),2.45(s,3H);ESIMS m/z 436.89[(M-H)-];IR(薄膜)3469,1686,1259,714cm-1。
(E)-2-溴-4-(3-(3,5-二氟-4-甲氧基苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d6)δ 13.48(bs,1H),8.03(s,1H),7.81(d,J=7.8Hz,1H),7.69(d,J=8.1Hz,1H),7.48(d,J=9.3Hz,2H),7.05(dd,J=15.6,9.0Hz,1H),6.83(d,J=15.9Hz,1H),4.86-4.74(m,1H),4.00(s,3H);EIMS m/z 451.18([M]+);IR(薄膜)3431,1132cm-1。
預示性地,化合物AI34、AI36-AI41、AI44-AI45(表1)可根據實例10或實例10及11中揭示之程序製造。
向經攪拌之(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲酸於DMF中之溶液中添加2,2,2-三氟乙胺、HOBt.H2O、EDC.HCl及DIPEA,且將反應混合物在25℃下攪拌18h。反應混合物用水稀釋且用EtOAc萃取。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;用己烷:EtOAc溶離)進行純化,得到白色半固體(110mg,50%):1H NMR(400MHz,CDCl3)7.40(m,2H),7.26(m,3H),6.56(d,J=16.0
Hz,1H),6.48(dd,J=16.0,8.0Hz,1H),5.82(br s,1H),4.08(m,3H),2.52(s,3H);ESIMS m/z 468.40([M-H]-);IR(薄膜)1657,1113,804cm-1。
化合物AC7-AC38、AC40-AC58、AC110-AC112、AC117及AC118(表1)根據實例12中揭示之程序製造。
向經攪拌之(嘧啶-5-基)甲胺(0.15g,1.43mmol)於CH2Cl2(10mL)中之溶液中逐滴添加三甲基鋁(2M甲苯溶液;0.71mL,1.43mmol),且將反應混合物在25℃下攪拌30min。在25℃下向反應混合物中逐滴添加4-((E)-3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲酸乙酯(0.3g,0.71mmol)於CH2Cl2中之溶液。將反應混合物在回流下攪拌18h,冷卻至25℃,用0.5N HCl溶液(50mL)淬滅且用EtOAc(2×50mL)萃取。合併之有機萃取物用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目;用配於正己烷之40% EtOAc溶離)純化,得到標題化合物(0.18g,55%):mp 141-144℃;1H(400MHz,CDCl3)δ 9.19(s,1H),8.79(s,2H),7.37(m,2H),7.23(m,2H),7.21(m,1H),6.57(d,J=16.0Hz,1H),6.40(dd,J=16.0,7.6Hz 1H),6.21(m,1H),4.65(s,2H),4.11(m,1H),
2.46(s,3H);ESIMS m/z 477.83([M-H]-)。
向經攪拌之甘胺醯胺(0.15g,0.58mmol)於CH2Cl2(5mL)中之溶液中逐滴添加三甲基鋁(2M甲苯溶液;1.45mL,2.91mmol),且將反應混合物在28℃下攪拌30min。在28℃下向反應混合物中逐滴添加(E)-2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸乙酯(0.3g,0.58mmol)於CH2Cl2(5mL)中之溶液。將反應混合物在回流下攪拌18h,冷卻至25℃,用1N HCl溶液(50mL)淬滅且用CH2Cl2(2×50mL)萃取。合併之有機萃取物用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目;用配於正己烷之40% EtOAc溶離)純化,得到呈黃色固體狀之標題化合物(0.15g,50%):mp 83-85℃;1H NMR(400MHz,CDCl3)δ 7.72(d,J=8.0Hz,1H),7.44(s,1H),7.40(s,2H),7.36(d,J=6.8Hz,1H),7.05(t,J=5.2Hz,1H),6.70(t,J=5.2Hz,1H),6.57(d,J=15.6Hz,1H),6.44(dd,J=15.6,8.0Hz,1H),4.23(d,J=5.6Hz,2H),4.15(m,1H),4.01(m,2H);ESIMS m/z 580.72([M-H]-)。
化合物AC59-AC75(表1)根據實例14中揭示之程序製造。
向經攪拌之(E)-2-溴-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)苯甲酸(300mg,0.638mmol)於CH2Cl2(5.0mL)中之溶液中依序添加2-胺基-N-(2,2,2-三氟乙基)乙醯胺(172mg,0.638mmol)以及PyBOP(364.5mg,0.701mmol)及DIPEA(0.32mL,1.914mmol),且將所得反應混合物在環境溫度下攪拌18h。反應混合物用水稀釋且用CH2Cl2萃取。合併之CH2Cl2層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之40% EtOAc溶離)進行純化,得到呈灰白色固體狀之標題化合物(121mg,31%):1H NMR(400MHz,CDCl3)δ 8.69(t,J=6.0Hz,1H),8.58(t,J=6.0Hz,1H),7.92(s,1H),7.87(d,J=6.4Hz,2H),7.62(d,J=8.4Hz,1H),7.45(d,J=8.4Hz,1H),7.0(m,1H),6.76(d,J=15.6Hz,1H),4.83(t,J=8.0Hz,1H),3.98(m,4H);ESIMS m/z 610.97([M+H]+);IR(薄膜)3303,1658,1166,817cm-1。
化合物AC76-AC80、AC96-AC102及AC113(表1)
根據實例15中揭示之程序製造。
向經攪拌之(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-氟-N-(硫雜環丁烷-3-基)苯甲醯胺(100mg,0.2159mmol)於丙酮/水(1:1,5.0mL)中之溶液中添加過硫酸氫鉀(266mg,0.4319mmol),且將所得反應混合物在環境溫度下攪拌4h。反應混合物用水稀釋且用EtOAc萃取。合併之EtOAc層經無水Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之30% EtOAc溶離)進行純化,得到呈灰白色固體狀之標題化合物(70.0mg,66%):1H NMR(400MHz,CDCl3)δ 8.07(t,J=8.4Hz,1H),7.39(t,J=1.6Hz,1H),7.31(d,J=1.2Hz,1H),7.26(m,2H),7.23(m,2H),7.19(d,J=1.6Hz,1H),6.60(d,J=16.8Hz,1H),6.49(dd,J=16.8,7.6Hz,1H),4.90(m,1H),4.64(m,2H),4.14(m,2H);ESIMS m/z 493.83([M-H]-);IR(薄膜)1527,1113,801,1167,1321cm-1。
化合物AC81-AC87(表1)根據實例16中揭示之程序製造。
將(E)-N-(2-(2-(環丙烷羰基)肼基)-2-側氧基乙基)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲醯胺(200mg,0.379mmol)於磷醯氯(POCl3,2.0mL)中之溶液在環境溫度下攪拌10min,接著將所得反應混合物加熱至50℃後持續1h。反應混合物在0℃下用冰水淬滅且用EtOAc萃取。合併之EtOAc層用飽和碳酸氫鈉(NaHCO3)溶液及鹽水溶液洗滌,經無水Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之50% EtOAc溶離)進行純化,得到呈淡棕色膠狀物質之標題化合物(70.0mg,36%):1H NMR(400MHz,CDCl3)δ 7.43(m,2H),7.27(m,2H),7.23(m,2H),6.58(d,J=16.0Hz,1H),6.41(dd,J=16.0,7.6Hz,1H),4.79(d,J=5.6Hz,2H),4.14(m,1H),2.48(s,3H),2.18(m,1H),1.16(m,4H);ESIMS m/z 509.89([M+H]+);IR(薄膜)1666,1166,1112,800cm-1。
在環境溫度下向經攪拌之(E)-2-溴-N-(2-側氧基-2-((2,2,2-三氟乙基)胺基)乙基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺(400mg,0.638mmol)於5mL THF中之溶液中一次性添加2,4-雙(4-甲氧基苯基)-1,3,2,4-二噻二磷雜環丁烷-2,4-二硫化物(勞森試劑(Lawesson's reagent))(336mg,0.830mmol)。將所得反應混合物攪拌18h。TLC展示反應不完全,因此再添加勞森試劑(168mg,0.415mmol),且將反應物攪拌48h。在利用TLC認為反應完全之後,在減壓下濃縮反應混合物。藉由急驟層析(SiO2,230-400篩目;用配於己烷之20% EtOAc溶離)進行純化,得到呈黃色玻璃狀油狀物之標題化合物(188mg,44.7%):1H NMR(400MHz,CDCl3)δ 8.34(m,1H),8.27(m,1H),7.60(d,J=1.6Hz,1H),7.49(d,J=8.0Hz,2H),7.40(s,2H),7.36(dd,J=8.2,1.7Hz,1H),6.53(d,J=16.0Hz,1H),6.38(dd,J=15.9,7.9Hz,1H),4.89(d,J=8.4,5.5Hz,2H),4.48(qd,J=9.0,6.0Hz,2H),4.11(m,1H);ESIMS m/z 656.9([M-H]-)。
在環境溫度下向經攪拌之(E)-2-溴-N-(2-側氧基-2-((2,2,2-三氟乙基)胺基)乙基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺(400mg,0.638mmol)於5mL THF中之溶液中一次性添加勞森試劑(64.5mg,0.160mmol)。將所得反應混合物攪拌18h,此後,在減壓下濃縮反應混合物。藉由急驟層析(SiO2,230-400篩目;用配於己烷之20% EtOAc溶離)進行純化,得到呈黃色油狀物之標題化合物(18.5mg,4.51%):1H NMR(400MHz,CDCl3)δ 8.18(t,J=5.0Hz,1H),7.58(d,J=1.6Hz,1H),7.47(d,J=8.0Hz,1H),7.40(s,2H),7.34(dd,J=8.1,1.6Hz,1H),6.52(m,2H),6.37(dd,J=15.9,7.9Hz,1H),4.54(d,J=4.9Hz,2H),4.12(m,1H),3.99(qd,J=8.9,6.5Hz,2H);ESIMS m/z 640.9([M-H]-)。
以下化合物根據實例19中揭示之程序製造。
(E)-2-溴-N-(2-硫酮基-2-((2,2,2-三氟乙基)胺基)乙基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺(AC92)
產物以無色油狀物分離(17.9mg,4.36%):1H
NMR(400MHz,CDCl3)δ 9.16(d,J=6.1Hz,1H),7.65(d,J=1.6Hz,1H),7.57(d,J=8.0Hz,1H),7.41(m,3H),7.21(t,J=5.6Hz,1H),6.55(d,J=15.9Hz,1H),6.41(dd,J=15.9,7.8Hz,1H),4.59(d,J=5.6Hz,2H),4.45(qd,J=9.0,6.0Hz,2H),4.12(q,J=7.2Hz,1H);ESIMS m/z 640.9([M-H]-)。
標題化合物根據實例88中揭示之程序製造,且以黃色黏性油狀物分離(416mg,23%):1H NMR(400MHz,CDCl3)δ 7.80(d,J=8.0Hz,1H),7.40(d,J=1.7Hz,1H),7.35(s,2H),7.12(dd,J=8.0,1.7Hz,1H),6.86(d,J=11.4Hz,1H),6.23-5.91(m,1H),4.42(q,J=7.1Hz,2H),4.33-4.10(m,1H),1.42(t,J=7.2Hz,3H);19F NMR(376MHz,CDCl3)δ -69.34(d,J=8.3Hz);EIMS m/z 514.10([M]-);IR(薄膜)2983,1727,1247,1204,1116cm-1。
向經攪拌之(Z)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸乙酯(360mg,0.70mmol)於CH3CN(1.0mL)中之溶液中添加碘三甲基矽烷(0.28mL,2.8mmol)。將反應混合物加熱至回流後持續20h,將其冷卻至環境溫度且分配於CH2Cl2與10%硫代硫酸鈉水溶液(Na2S2O3)之間。有機相用10% Na2S2O3水溶液洗滌一次且經硫酸鎂(MgSO4)乾燥且在真空中濃縮。依序用配於己烷之10% EtOAc及配於CH2Cl2之20% MeOH)作為溶離溶劑,使該物質經由二氧化矽短柱流過,得到呈黃色泡沫狀之標題化合物(143mg,42%):mp 54-64℃;1H NMR(400MHz,CDCl3)δ 11.36(s,1H),7.99(d,J=8.0Hz,1H),7.43(s,1H),7.30(s,2H),7.14(d,J=7.9Hz,1H),6.85(d,J=11.4Hz,1H),6.15(t,J=10.9Hz,1H),4.36-4.09(m,1H);19F NMR(376MHz,CDCl3)δ -69.30。
向經攪拌之(Z)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸(200mg,0.41mmol)於無水THF(5.0mL)中之溶液中添加羰基二咪唑(82mg,0.51mmol)。將混合物在50℃油浴中加熱1.5h,用2-胺基
-N-(2,2,2-三氟乙基)乙醯胺鹽酸鹽(109mg,0.057mmol)處理,且將所得混合物加熱至回流後持續8h。在冷卻至環境溫度之後,將混合物吸收於Et2O中且用5%硫酸氫鈉水溶液(NaHSO4)洗滌兩次(2×)且用飽和NaCl洗滌一次(1×)。經MgSO4乾燥後,在真空中濃縮且藉由二氧化矽中壓層析用配於己烷之EtOAc作為溶離劑進行純化,獲得呈白色泡沫狀之標題化合物(160mg,41%)。mp 48-61℃:1H NMR(400MHz,CDCl3)δ 7.58(d,J=7.9Hz,1H),7.44-7.29(m,3H),7.14(dd,J=7.9,1.6Hz,1H),6.86(d,J=11.4Hz,1H),6.76(t,J=5.9Hz,1H),6.59(br s,1H),6.21-6.04(m,1H),4.23(d,J=5.5Hz,1H),3.98(qd,J=9.0,6.5Hz,2H);19F NMR(376MHz,CDCl3)δ -69.31,-72.3;EIMS m/z 626.9([M+1]+)。
在0℃下將(E)-4-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)哌啶-1-甲酸第三丁酯(0.75g,1.11mmol)添加至二噁烷鹽酸鹽(10mL)中且攪拌18h。反應混合物在減壓下濃縮且用乙醚濕磨,得到呈淡棕色固體狀之化合物(0.6g,88%)。
向經攪拌之(E)-2-溴-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.1g,0.16mmol)於CH2Cl2(10.0mL)中之溶液中添加TEA(0.046mL,0.35mmol)且攪拌10min。接著在環境溫度下添加乙醯氯(0.014,0.18mmol),且攪拌16h。反應混合物用CH2Cl2稀釋且用NaHCO3飽和溶液及鹽水溶液洗滌。合併之CH2Cl2層經Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物用5% Et2O/正戊烷洗滌,得到呈白色固體狀之標題化合物(0.054g,50%)。
在環境溫度下向經攪拌之3,3,3-三氟丙酸(0.02g,0.16mmol)於CH2Cl2(10.0mL)中之溶液中添加(E)-2-溴
-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.1g,0.16mmol)、PYBOP(0.09g,0.17mmol)及DIPEA(0.06g,0.48mmol)。將反應混合物在環境溫度下攪拌5h。反應混合物用CH2Cl2稀釋。合併之CH2Cl2層用3N HCl及NaHCO3飽和溶液洗滌,經分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物藉由管柱層析(SiO2,100-200篩目;用2% MeOH/CH2Cl2溶離)純化,得到呈灰白色膠狀物質之標題化合物(0.035g,29%)。
向經攪拌之(E)-2-溴-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.1g,0.16mmol)於THF(5.0mL)中之溶液中添加TEA(0.06mL,0.64mmol)且攪拌10min。接著在環境溫度下添加三氟甲磺酸2,2,2-三氟乙酯(0.03,0.16mmol)且攪拌16h。反應混合物用EtOAc稀釋且用NaHCO3飽和溶液及鹽水溶液洗滌。合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,得到呈棕色固體狀之標題化合物(0.05g,44%)。
將(E)-2-溴-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.1g,0.16mmol)、甲醛(30%於水中)(0.1mL,0.16mmol)及AcOH(0.01mL)於MeOH(5.0mL)中之溶液在環境溫度下攪拌30min。此後,在0℃下添加NaBH3CN(0.01g,0.16mmol),且將反應物在環境溫度下攪拌8h。在減壓下移除溶劑,獲得殘餘物,該殘餘物用EtOAc稀釋且用飽和NaHCO3水溶液及鹽水溶液洗滌。合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,獲得殘餘物,該殘餘物用Et2O/戊烷濕磨,得到呈淺黃色膠狀物質之標題化合物(0.06g,59%)。
向經攪拌之(E)-2-溴-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.25g,0.43
mmol)於THF(10.0mL)中之溶液中添加TEA(0.16mL,1.29mmol)且將反應物攪拌10min。接著添加2-溴乙腈(0.07,0.65mmol),且將反應物在環境溫度下攪拌8h。反應混合物用EtOAc稀釋且用飽和鹽水溶液洗滌。合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,得到呈灰白色固體狀之標題化合物(0.125g,46.8%)。
將(E)-2-溴-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.2g,0.35mmol)、氧雜環丁烷-3-酮(0.027g,0.38mmol)及AcOH(0.01mL)於MeOH(5.0mL)中之溶液在環境溫度下攪拌30min。此後,在0℃下經10min之時間分批緩慢添加NaBH3CN(0.022g,0.35mmol),且將反應物在環境溫度下攪拌8h。在減壓下移除溶劑,獲得殘餘物,該殘餘物用EtOAc稀釋且用NaHCO3飽和溶液及鹽水溶液洗滌。合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,獲得殘餘物,該殘餘物用Et2O/戊烷濕磨,得到呈灰白色固體狀之標題化合物(0.05g,23%)。
向經攪拌之(E)-2-溴-N-(哌啶-4-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(0.25g,0.43mmol)於THF(10.0mL)中之溶液中添加TEA(0.16mL,1.29mmol)且將反應物攪拌10min。接著添加2-氯乙醇(0.05,0.65mmol),且將反應物在環境溫度下攪拌8h。反應混合物用EtOAc稀釋且用飽和鹽水溶液洗滌。合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,得到呈灰白色固體狀之標題化合物(0.09g,34%)。
向經攪拌之(E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)乙酸第三丁酯(440mg,0.734mmol)於CH2Cl2(36.0mL)中之溶液中添加TFA(4.0
mL),且將反應混合物在環境溫度下攪拌1h。在減壓下濃縮反應混合物,獲得殘餘物,該殘餘物用正戊烷洗滌,得到呈灰白色固體狀之標題化合物(310mg,78%):1H NMR(400MHz,CDCl3)δ 13.0(s,1H),8.75(t,J=5.7Hz,1H),7.93(m,2H),7.62(d,J=7.5Hz,1H),7.40(d,J=8.1Hz,1H),6.96(dd,J=15.3,9.3Hz,1H),6.78(d,J=15.3Hz,1H),4.83(m,1H),3.90(d,J=5.7Hz,2H);ESIMS m/z 543.61([M+H]+);IR(薄膜)3429,1635,1114,772cm-1。
向經攪拌之(E)-N-((6-氯吡啶-3-基)甲基)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯基)-2-甲基苯甲醯胺(0.06g,0.117mmol)於甲苯(3mL)中之溶液中添加勞森試劑(0.14g,0.351mmol),且將反應物在100℃下照射1h,接著冷卻至環境溫度且在減壓下濃縮,得到粗化合物。粗產物藉由製備型HPLC純化,得到呈黃色固體狀之產物(0.03g,49%)。
步驟1. 2-(三氟甲氧基)-4-乙烯基苯甲酸(AI79):向經攪拌之4-溴-2-(三氟甲氧基)苯甲酸(1g,3.67mmol)於DMSO(20mL)中之溶液中添加乙烯基三氟硼酸鉀(1.47g,11.02mmol)及K2CO3(1.52g,11.02mmol)。反應混合物用氬氣脫氣30min。
添加二氯化雙三苯基膦(二苯基膦基二茂鐵)鈀(0.13g,0.18mmol),且將反應混合物加熱至80℃後持續1h。反應混合物用水(100mL)稀釋,用EtOAc(2×50mL)萃取,用鹽水洗滌且經Na2SO4乾燥。在減壓下濃縮,得到粗化合物,該粗化合物藉由急驟管柱層析純化,得到呈淺黃色膠狀物質之產物(0.4g,47%):1H NMR(400MHz,CDCl3)δ 8.05(d,J=8.1Hz,1H),7.44(d,J=1.8Hz,1H),7.35(s,1H),6.78(dd,J=17.4.1,11.1Hz,1H),5.92(d,J=17.4Hz,1H),5.51(d,J=10.8Hz,1H);ESIMS m/z 232.97([M+H]+)。
步驟2. (E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-(三氟甲氧基)苯甲酸(AI80):向經攪拌之2-(三氟甲氧基)-4-乙烯基苯甲酸(0.356g,1.53mmol)於1N甲基吡咯啶(5.0mL)中之溶液中添加1-(1-溴-2,2,2-三氟乙基)-3,5-二氯-4-氟苯(1.0g,3.07mmol)、CuCl(0.03g,0.307mmol)及2,2-聯吡啶(0.095g,0.614mmol)。將反應混合物在150℃下攪拌1h。根據TLC反應完全後,反應混合物用水
(100mL)稀釋且用EtOAc(2×50mL)萃取。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,獲得粗化合物,該粗化合物藉由急驟管柱層析純化,得到呈淺黃色膠狀物質之產物(0.3g,21%):1H NMR(400MHz,CDCl3)δ 8.08(d,J=8.0Hz,1H),7.45(d,J=1.6Hz,1H),7.35(s,3H),6.63(d,J=16.0Hz,1H),6.50(dd,J=16.0,8.0Hz,1H),4.15(m,1H);ESIMS m/z 474.81([M-H]-)。
步驟3. (E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-N-(2-側氧基-2-(2,2,2-三氟乙基胺基)乙基)-2-(三氟甲氧基)苯甲醯胺(AC116):將(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-(三氟甲氧基)苯甲酸(0.25g,0.52mmol)、2-胺基-N-(2,2,2-三氟乙基)乙醯胺(0.158g,0.62mmol)、PyBOP(0.40g,0.78mmol)及DIPEA(0.134g,1.04mmol)於CH2Cl2(10.0mL)中之混合物在環境溫度下攪拌16h。反應混合物用水稀釋且用CH2Cl2萃取。合併之CH2Cl2層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之20% EtOAc溶離)進行純化,得到呈淺黃色膠狀物質之標題化合物(0.15g,47%)。
以下分子根據實例118之步驟2中揭示之程序製造:
(E)-4-(3-(3,5-二溴苯基)-4,4,4-三氟丁-1-烯-1-基)-2-甲基苯甲酸
標題分子以棕色固體狀分離:1H NMR(400MHz,DMSO-d 6)δ 12.90(bs,1H),7.85(s,1H),7.78-7.75(m,3H),7.47-7.41(m,2H),6.89(dd,J=15.6,9.2Hz,1H),6.72(d,J=15.6Hz,1H),4.80-4.75(m,1H),2.33(s,3H);ESIMS m/z 474.90([M-H]-);IR(薄膜)3437,1689,1165,579cm-1。
(E)-4-(3-(3,5-二溴苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.5(bs,1H),8.03(s,1H),7.95-7.85(m,4H),7.81(d,J=7.8Hz,1H),7.14(dd,J=15.6,9.6Hz,1H),6.90(d,J=15.9Hz,1H),4.86-4.79(m,1H);ESIMS m/z 528.82([M-H]+);IR(薄膜)3437,1707,1153,555cm-1。
(E)-2-溴-4-(3-(3,5-二溴苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(400MHz,
DMSO-d 6)δ 13.90(bs,1H),7.98(s,1H),7.88(s,1H),7.84(s,2H),7.74(d,J=7.6Hz,1H),7.64(d,J=8.8Hz,1H),7.04(dd,J=15.6,8.8Hz,1H),6.78(d,J=15.6Hz,1H),4.80-4.78(m,1H);ESIMS m/z 538.74([M-H]-);IR(薄膜)3424,1695,1168,578cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(3-氟-5-(三氟甲基)苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(400MHz,DMSO-d 6)δ 13.3(bs,1H),7.93(s,1H),7.82-7.77(m,2H),7.72-7.66(m,2H),7.59(d,J=8.0Hz,1H),7.03(dd,J=15.6,9.2Hz,1H),6.76(d,J=15.6Hz,1H),4.94-4.90(m,1H);ESIMS m/z 469.02([M-H]-);IR(薄膜)3444,1704,1172,513cm-1。
(E)-4-(3-(3,5-雙(三氟甲基)苯基)-4,4,4-三氟丁-1-烯-1-基)-2-溴苯甲酸
標題分子以棕色固體狀分離:1H NMR(400MHz,CDCl3)δ 7.98(d,J=7.6Hz,1H),7.92(s,1H),7.83(s,2H),7.73(d,J=1.6Hz,1H),7.42-7.40(m,1H),6.62(d,J=16.4
Hz,1H),6.55(dd,J=16.0,8.0Hz,1H),4.40-4.30(m,1H);ESIMS m/z 518.94([M-H]-);IR(薄膜)3447,1705,1171,526cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(3-(三氟甲基)苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.50(bs,1H),7.97-7.87(m,3H),7.78-7.61(m,4H),7.08(dd,J=15.9,9.3Hz,1H),6.81(d,J=15.9Hz,1H),4.97-4.84(m,1H);ESIMS m/z 518.94([M-H]-);IR(薄膜)3447,1705,1171,526cm-1。
(E)-2-溴-4-(3-(3-氯-5-(三氟甲基)苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以淺黃色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.9(s,1H),8.03(s,1H),7.96-7.91(m,3H),7.72(d,J=8.1Hz,1H),7.63-7.60(m,1H),7.11(dd,J=15.9,9.6Hz,1H),6.79(d,J=15.9Hz,1H),4.98-4.91(m,1H);ESIMS m/z 484.94([M-H]-);IR(薄膜)3444,1705,1171,764cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(4-氟-3-(三氟甲基)苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,CDCl3)δ 8.00(d,J=8.1Hz,1H),7.71(s,1H),7.61-7.59(m,2H),7.41(d,J=8.1Hz,1H),7.30-7.24(m,1H),6.59(dd,J=16.2,6.0Hz,1H),6.48(d,J=16.5Hz,1H),4.26-4.21(m,1H);ESIMS m/z 469.0([M-H]-);IR(薄膜)3444,1699,1327cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氟苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.60(bs,1H),7.97(s,2H),7.72(d,J=7.2Hz,1H),7.41-7.31(m,2H),7.04(dd,J=15.6,9.0Hz,1H),6.71(d,J=15.9Hz,1H),4.15-4.11(m,1H);ESIMS m/z 438.8([M+H]+)。
(E)-4-(4,4,4-三氟-3-(2,3,4-三氟苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 8.00(s,1H),7.93(d,J=8.4Hz,1H),7.81(d,J=8.1Hz,1H),7.63-7.60(m,1H),7.47-7.44(m,1H),7.02-7.01(m,1H),5.10-4.90(m,1H)。
(E)-2-溴-4-(4,4,4-三氟-3-(2,3,4-三氟苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離,且將粗酸直接用於下一步驟:1H NMR(300MHz,DMSO-d 6)δ 13.65(bs,1H),7.95(s,1H),7.75(d,J=7.8Hz,1H),7.62-7.59(m,2H),7.50(dd,J=15.6,9.0Hz,1H),6.95(d,J=15.9Hz,1H),4.86-4.74(m,1H);ESIMS m/z 436.92([M-H]-);IR(薄膜)3445,1641,1116cm-1。
(E)-4-(4,4,4-三氟-3-(2,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,
DMSO-d 6)δ 13.6(s,1H),8.04(s,1H),7.96(d,J=8.4Hz,3H),7.83(d,J=8.1Hz,1H),7.17-7.03(m,2H),5.16-5.05(m,1H);ESIMS m/z 476.9([M-H]-);IR(薄膜)3436,1651,1116,661cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(2,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ(300MHz,DMSO-d 6)δ 13.4(s,1H),7.99(d,J=10.2Hz,3H),7.76(d,J=8.1Hz,1H),7.65(d,J=7.8Hz,1H),7.09-6.91(m,2H),5.11-5.05(m,1H);ESIMS m/z 486.8([M-H]-);IR(薄膜)3436,1651,1115,737cm-1。
(E)-4-(3-(4-氯-3-硝基苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離,且將粗酸直接用於下一步驟:1H NMR(300MHz,DMSO-d 6)13.80(bs,1H),8.33(s,1H),7.94-7.81(m,5H),7.75-7.72(m,1H),7.06(dd,J=15.9,8.7Hz,1H),6.90(d,J=15.9Hz,1H),5.02-4.81(m,1H)。
(E)-2-溴-4-(3-(4-氯-3-硝基苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)13.50(bs,1H),8.31(s,1H),8.00-7.77(m,3H),7.75-7.72(m,1H),7.63-7.55(m,1H),7.03(dd,J=15.9,9.0Hz,1H),6.81(d,J=15.9Hz,1H),5.04-4.91(m,1H)。
;ESIMS m/z 462.16([M-H]-);IR(薄膜)3428,1697,1113,749cm-1。
(E)-4-(4,4,4-三氟-3-(4-氟-3,5-二甲基苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 7.96(s,1H),7.92(d,J=8.4Hz,1H),7.80-7.75(m,1H),7.27(d,J=6.9Hz,2H),6.96(dd,J=15.6,8.7Hz,1H),6.87(d,J=15.6Hz,1H),4.68-4.56(m,1H),2.23(s,6H);ESIMS m/z 419.03([M-H]-);IR(薄膜)3445,2928,1713,1146cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(4-氟-3,5-二甲基苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 7.91(s,1H),7.74(d,J=7.8Hz,1H),7.61-7.58(m,1H),7.26(d,J=6.6Hz,2H),6.93(dd,J=159,8.7Hz,1H),6.87(d,J=15.9Hz,1H),4.59-4.53(m,1H),2.23(s,6H);ESIMS m/z 428.97([M-H]-);IR(薄膜)3473,1701,1111,581cm-1。
(E)-4-(4,4,4-三氟-3-(4-氟-3-甲基苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.58(bs,1H),7.98(s,1H),7.92-7.90(m,1H),7.80(d,J=8.1Hz,1H),7.48-7.45(m,1H),7.42-7.37(m,1H),7.22-7.16(m,1H),7.04(dd,J=15.9,8.7Hz,1H),6.88(d,J=15.9Hz,1H),4.70-4.60(m,1H),4.04-3.99(m,1H),2.26(s,3H);ESIMS m/z 405.05([M-H]-);IR(薄膜)3437,1710,1145cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(4-氟-3-甲基苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.39(bs,1H),7.91(s,1H),7.72(d,J=8.1Hz,1H),7.61-7.58(m 1H),7.47-7.44(m,1H),7.38-7.36(m,1H),7.18(t,J=9.6Hz,1H),6.95(dd,J=15.6,8.7Hz,1H),6.76(d,J=15.9Hz,1H),4.67-4.61(m,1H),2.25(s,3H);ESIMS m/z 415.0([M-H]-);IR(薄膜)3435,2989,1700,1260cm-1。
(E)-4-(3-(3,5-二氯苯基)-4,4,5,5,5-五氟戊-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色半固體狀分離:1H NMR(400MHz,DMSO-d 6)δ 13.70(bs,1H),8.01(s,1H),7.91(s,1H),7.80(d,J=8.4Hz,1H),7.72(J=1.6Hz,2H),7.66(t,J=3.2Hz,1H),7.15(dd,J=15.6,9.6Hz,1H),6.91(d,J=15.6Hz,1H),4.86-4.78(m,1H);ESIMS m/z 491.0([M-H]-);IR(薄膜)3446,1712,1141,749cm-1。
(E)-2-溴-4-(3-(3,5-二氯苯基)-4,4,5,5,5-五氟戊-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(400MHz,DMSO-d 6)δ 7.85(s,1H),7.70(s,2H),7.65-7.64(m,1H),7.56-7.52(m,2H),6.94(d,J=9.2Hz,1H),6.76(d,J=16Hz,1H),4.82-4.80(m,1H);ESIMS m/z 500.8([M-H]-);IR(薄膜)3422,1683,1184,750,575cm-1。
(E)-4-(3-(3,4-二溴苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.5(bs,1H),8.01-7.99(m,2H),7.94-7.91(m,1H),7.85-7.78(m,2H),7.53-7.50(m,1H),7.09(dd,J=15.6,8.7Hz,1H),6.89(d,J=15.9Hz,1H),4.85-4.78(m,1H);ESIMS m/z 528.8([M-H]-);IR(薄膜)3437,1722,1168cm-1。
(E)-2-溴-4-(3-(3,4-二溴苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,
DMSO-d 6)δ 13.38(bs,1H),7.98-7.96(m,2H),7.84(d,J=8.4Hz,1H),7.74(d,J=8.1Hz,1H),7.63-7.61(m,1H),7.51-7.49(m,1H),7.01(dd,J=15.9,9.0Hz,1H),6.78(d,J=15.6Hz,1H),4.82-4.76(m,1H);ESIMS m/z 538.8([(M-H]-);IR(薄膜)3446,1699,1166,581cm-1。
(E)-4-(4,4,4-三氟-3-(3-(三氟甲氧基)苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色半固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 8.01(s,1H),7.94(d,J=8.7Hz,1H),7.80(d,J=8.1Hz,1H),7.63-7.55(m,3H),7.41(d,J=7.5Hz,1H),7.11(dd,J=15.6,9.0Hz,1H),6.92(d,J=15.9Hz,1H),4.89-4.82(m,1H);ESIMS m/z 456.98([M-H]-);IR(薄膜)3413,1668,1161cm-1。
(E)-2-溴-4-(4,4,4-三氟-3-(3-(三氟甲氧基)苯基)丁-1-烯-1-基)苯甲酸
標題分子以棕色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 7.73(s,1H),7.59(m,3H),7.44(s,1H),7.40(d,J=7.6Hz,2H),6.88(dd,J=15.6,9.0Hz,1H),6.73(d,J=
15.9Hz,1H),4.85-4.82(m,1H);ESIMS m/z 466.93([M-H]-);IR(薄膜)3437,1703,1111cm-1。
(E)-4-(3-(3-氰基-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.60(bs,1H),8.21-8.19(m,1H),8.01-7.91(m,3H),7.81(d,J=8.4Hz,1H),7.12(dd,J=15.9,8.1Hz,1H),6.91(d,J=15.6Hz,1H),4.92-4.86(m,1H);ESIMS m/z 416.27([M-H]-);IR(薄膜)3429,2238,1713,1116cm-1。
(E)-2-溴-4-(3-(3-氰基-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.56(bs,1H),8.21-8.18(m,1H),8.00-7.95(m,2H),7.73-7.59(m,3H),7.03(dd,J=15.9,9.3Hz,1H),6.79(d,J=15.3Hz,1H),4.87-4.84(m,1H);ESIMS m/z 426.0([M-H]-)。
(E)-2-溴-4-(3-(3,4-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.4(s,1H),7.96(d,J=1.2Hz,1H),7.88(d,J=1.8Hz,1H),7.74-7.68(m,2H),7.63(dd,J=8.1,1.2Hz,1H),7.57(dd,J=8.4,1.8Hz,1H),7.02(dd,J=15.9,9.3Hz,1H),6.78(dd,J=5.9Hz,1H),4.84-4.78(m,1H);ESIMS m/z 451.0([M-H]-);IR(薄膜)3445,1704,1113,740cm-1。
(E)-4-(3-(3-溴-5-氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.50(bs,1H),7.91(s,1H),7.86-7.64(m,5H),7.06(dd,J=15.9,9.0Hz,1H),6.87(d,J=15.9Hz,1H),4.85-4.78(m,1H);ESIMS m/z 485.17([M-H]-);IR(薄膜)3438,1708,1114,774,516cm-1。
(E)-2-溴-4-(3-(3-溴-5-氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.38(bs,1H),7.98(s,1H),7.80-7.72(m,4H),7.64-7.61(m,1H),7.06(dd,J=15.9,9.3Hz,1H),6.79(d,J=15.6Hz,1H),4.88-4.80(m,1H);ESIMS m/z 495.05([M-H]-);IR(薄膜)3436,1699,1116,750,531cm-1。
(E)-4-(3-(3-溴-5-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.6(bs,1H),8.02(s,1H),7.91-7.89(m,1H),7.81(d,J=8.0Hz,1H),7.69(s,1H),7.63-7.59(m,1H),7.55(d,J=9.3Hz,1H),7.11(dd,J=15.9,9.0Hz,1H),6.91(d,J=15.9Hz,1H),4.87-4.80(m,1H);ESIMS m/z 469.07([M-H]-);IR(薄膜)3428,1712,1171,523cm-1。
(E)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸
標題分子以黃色固體狀分離:1H NMR(400MHz,CDCl3)δ 8.18-8.03(m,2H),7.49(d,J=8.3Hz,2H),7.42(s,2H),6.66(d,J=15.9Hz,1H),6.47(dd,J=15.9,8.0Hz,1H),4.13(p,J=8.6Hz,1H);19F NMR(376MHz,CDCl3)δ
-68.65;ESIMS m/z 409.1([M-H]-)。
(E)-2-溴-4-(3-(3-氯-4-甲基苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.30(bs,1H),7.93(d,J=1.2Hz,1H),7.42(d,J=8.1Hz,1H),7.62(dd,J=1.5,8.1Hz,1H),7.53(s,1H),7.48(d,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),6.96(dd,J=15.6,8.7Hz,1H),6.77(d,J=15.6Hz,1H),4.73-4.61(m,1H),2.35(s,3H);ESIMS m/z 431.77([M-H]-);IR(薄膜)3435,1701,1111,750cm-1。
(E)-4-(3-(3-氯-4-甲基苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.50(bs,1H),7.98(s,1H),7.92(d,J=8.1Hz,1H),7.80(d,J=8.1Hz,1H),7.53(s,1H),7.48(d,J=8.1Hz,1H),7.40(d,J=8.4Hz,1H),7.04(dd,J=15.6,8.4Hz,1H),6.88(d,J=15.6Hz,1H),4.72-4.66(m,1H),2.35(s,3H);ESIMS m/z 421.82([M-H]-);IR(薄膜)3460,2926,1712,
1170,750cm-1。
(E)-4-(4,4,5,5,5-五氟-3-(3,4,5-三氯苯基)戊-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以深棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.6(bs,1H),8.03(s,1H),7.95-7.86(m,3H),7.81(d,J=8.1Hz,1H),7.16(dd,J=15.3,9.3Hz,1H),6.92(d,J=15.6Hz,1H),4.95-4.88(m,1H);19F NMR(300MHz,DMSO-d 6)δ -80.35,-58.02;ESIMS m/z 526.8([M+H]+)。
(E)-2-溴-4-(4,4,5,5,5-五氟-3-(3,4,5-三氯苯基)戊-1-烯-1-基)苯甲酸
標題分子以深棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.6(bs,1H),7.94(s,2H),7.78(d,J=7.8Hz,1H),7.71(d,J=7.8Hz,1H),7.60(d,J=7.5Hz 1H),7.07(dd,J=15.0,8.7Hz,1H),6.79(d,J=15.6Hz,1H),4.93-4.78(m,1H);ESIMS m/z 538.9([M+H]+);IR(薄膜)3420,1602,1123,746cm-1。
(E)-2-溴-4-(3-(4-氰基-3,5-二氟苯基)-4,4,4-三氟丁-1-烯
-1-基)苯甲酸
標題分子以棕色膠狀物分離:ESIMS m/z 443.91([M-H]-);IR(薄膜)3447,2244,1703,1114cm-1。
(E)-2-氯-4-(3-(3,5-二溴苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(300MHz,DMSO-d 6)δ 13.39(bs,1H),7.95-7.70(m,5H),7.61(d,J=8.1Hz,1H),7.07(dd,J=15.6,9.3Hz,1H),6.80(d,J=15.6Hz,1H),4.84-4.78(m,1H);ESIMS m/z 496.77([M-H]-);IR(薄膜)3439,2920,1707,1165cm-1。
(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以灰白色固體狀分離:mp 140-143℃;1H NMR(400MHz,DMSO)δ13.60(bs,1H),8.02(s,1H),7.94-7.90(m,1H),7.88-7.86(m,2H),7.81-7.79(m,1H),
7.12(dd,J=15.6,8.8Hz,1H),6.89(d,J=15.6Hz,1H),4.86-4.81(m,2H);ESIMS m/z 458.88([M-H]-)。
(E)-4-(3-(3,4-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以淡橙色結晶固體狀分離(875mg,88%):1H NMR(400MHz,CDCl3)δ 12.35(s,1H),8.08(d,J=8.4Hz,2H),7.55-7.41(m,4H),7.24(dd,J=8.3,2.1Hz,1H),6.64(d,J=15.8Hz,1H),6.51(dd,J=15.9,7.7Hz,1H),4.15(p,J=8.7Hz,1H);19F NMR 376MHz,CDCl3)δ -68.75;ESIMS m/z 375([M+H]+)。
(E)-4-(3-(3,4-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(400MHz,DMSO-d 6)δ 13.6(s,1H),8.02(s,1H),7.93-7.89(m,2H),7.80(d,J=7.6Hz,1H),7.73(d,J=8.4,Hz,1H),7.58(dd,J=8.4,2.0Hz,1H),7.09(dd,J=15.6,8.8,Hz,1H),6.89(d,J=15.6,Hz,1H),4.86-4.81(m,1H);ESIMS m/z 441.0([M-H]-);IR(薄膜)3447,1710,1169,749cm-1。
(E)-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三
氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 13.6(bs,1H),7.98(s,1H),7.91(d,J=7.8Hz 1H),7.75-7.66(m,1H),7.10(dd,J=15.6,9.0Hz,1H),6.89(d,J=15.9Hz 1H),4.86-4.80(m,1H);ESIMS m/z 441.1([M-H]-);IR(薄膜)3460,2928,1721,1170,764cm-1。
(E)-4-(3-(3,4-二氯-5-甲基苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以淺黃色半固體狀分離:1H NMR(400MHz,DMSO-d6)δ 13.58(bs,1H),8.00(s,1H),7.93(d,J=8.4Hz,1H),7.80(d,J=8.4Hz,1H),7.72(s,1H),7.55(s,1H),7.07(dd,J=16.4,9.6Hz,1H),6.89(d,J=15.6Hz,1H),4.78-4.73(m,1H),2.42(s,3H);ESIMS m/z 455.0([M-H]-);IR(薄膜)1713,1170,750cm-1。
(E)-2-溴-4-(3-(3,4-二氯苯基)-4,4-二氟戊-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(400MHz,DMSO-d6)δ 13.3(s,1H),7.92(s,1H),7.77-7.71(m,2H),7.68-7.63(m,1H),7.61-7.60(m,1H),7.60-7.58(m,1H),6.98(dd,J=15.6,9.2Hz,1H),6.65(d,J=15.6Hz,1H),4.83-4.80(m,1H),1.59-1.54(m,3H);ESIMS m/z 448.8([M-H]-)。
(E)-2-溴-4-(3-(3-氯-5-乙基苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色液體狀分離:1H NMR(400MHz,DMSO-d6)δ 13.4(bs,1H),7.97(s,2H),7.91(s,1H),7.74(d,J=8.4Hz,2H),7.66-7.61(m,1H),7.03(dd,J=16.0,8.4Hz,1H),6.8(d,J=15.6Hz,1H),4.89-4.84(m,1H),2.66-2.65(m,2H),1.25(t,J=9.2Hz,3H);ESIMS m/z 446.8([M+H]+)。
(E)-2,6-二甲基-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)
丁-1-烯基)苯甲酸.
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d6)δ 13.1(s,1H),7.87(s,2H),7.27(s,2H),6.81(dd,J=15.6,8.7Hz,1H),6.69(d,J=15.3Hz,1H),4.85-4.79(m,1H),2.27(s,6H);ESIMS m/z 437.01([M-H]-);IR(薄膜)3285,1621,1162,954cm-1。
(E)-2-溴-4-(3-(3,5-二溴-4-氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d6)δ 13.40(bs,1H),8.07(d,J=7.5Hz,1H),7.94-7.89(m,2H),7.66-7.60(m,2H),7.10(dd,J=8.7,16.0Hz,1H),6.96(d,J=15.6Hz,1H),4.82-4.80(m,1H);ESIMS m/z 574.7([M+H]+)。
(E)-4-(3-(3,5-二溴-4-氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,
DMSO-d6)δ 13.36(bs,1H)8.05(s,2H),7.95(d,J=8.1Hz,1H),7.87-7.67(m,2H),7.14(dd,J=9.0,15.6Hz,1H),6.96(d,J=15.6Hz,1H),4.88-4.82(m,1H);ESIMS m/z 564.58([M+H]+)。
(E)-2-溴-4-(3-(4-溴-3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d6)δ 13.40(bs,1H),7.98(s,1H),7.87(s,2H),7.75(d,J=8.1Hz,1H),7.65-7.62(m,1H),7.06(dd,J=15.9,9.3Hz,1H),6.80(d,J=15.9Hz,1H),4.87-4.80(m,1H);ESIMS m/z 518.9([M-H]-)。
(E)-4-(3-(4-溴-3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(三氟甲基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(300MHz,DMSO-d6)δ 13.6(bs,1H)8.03(s,1H),7.95(d,J=8.4Hz,1H),7.88(s,2H),7.81(d,J=8.1Hz,1H),7.13(dd,J=16.2,7.5Hz,1H),6.91(d,J=15.9Hz,1H),4.89-4.83(m,1H);ESIMS m/z 532.0([M+H]+)。
(E)-2-溴-4-(3-(3-氯-4-(三氟甲氧基)苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲酸
標題分子以棕色膠狀物分離:1H NMR(400MHz,DMSO-d6)δ 13.36(bs,1H)7.95(s,1H),7.73(d,J=7.6Hz,1H),7.63(d,J=8.1Hz,1H),7.46(s,1H)7.35-7.31(m,2H),7.04(dd,J=16.0,8.8Hz,1H),6.78(d,J=16.4Hz,1H),4.71-4.68(m,1H);ESIMS m/z 500.8([M-H]-)。
向經攪拌之5-溴-2,3-二氫-1H-茚-1-酮(5g,23.7mmol)於甲苯中之溶液中添加乙烯基酸酐吡啶複合物(8.55g,35.54mmol)、Pd(PPh3)4(0.1g,0.094mmol)、K2CO3(22.88g,165.83mmol)。將所得反應混合物在回流下加熱16h。將反應混合物冷卻至25℃且過濾,且在減壓下濃縮濾液。殘餘物用EtOAc稀釋且用水及鹽水洗滌。合併之有機萃取物經無水Na2SO4乾燥且在減壓下濃縮。所獲得之殘餘物藉由急驟管柱層析(SiO2,配於石油醚之5% EtOAc)純化,得到呈固體狀之標題化合物(1.8g,48%):1H NMR(400MHz,CDCl3)δ 7.74(d,J=7.2Hz,1H),7.49(br s,1H),7.44(d,J=7.2Hz,1H),6.82(m,1H),5.90(d,J=7.4Hz,
1H),5.42(d,J=6.4Hz,1H),3.20(m,2H),2.70(m,2H);ESIMS m/z 159.06([M+H]-)。
以下化合物根據實例20中揭示之程序製造。
6-乙烯基-3,4-二氫萘-1(2H)-酮(BI2)
產物以灰白色固體狀分離(5g,48%):1H NMR(400MHz,DMSO-d 6)δ 7.85(d,J=8.4Hz,1H),7.48(m,2H),6.82(m,1H),6.02(d,J=7.4Hz,1H),5.44(d,J=6.4Hz,1H),2.95(m,2H),2.60(m,2H),2.00(m,2H);ESIMS m/z 173.14([M-H]-);IR(薄膜)1681cm-1。
將含5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(4g,11.7mmol)、5-乙烯基-2,3-二氫-1H-茚-1-酮(0.92g,5.8mmol)、CuCl(0.115g,1.171mmol)及2,2-聯吡啶(0.053g,0.34mmol)之1,2-二氯苯(25mL)在180℃下加熱16h。將反應混合物冷卻至25℃且在減壓下濃縮。殘餘物藉由急驟管柱層析(SiO2,配於石油醚之5% EtOAc)純化,得到呈液體狀之標題化合物(1.28g,25%):1H NMR(400MHz,CDCl3)δ 7.76(d,J=7.4Hz,1H),7.52(m,3H),6.68(d,J=7.4Hz,
1H),6.52(m,1H),4.18(m,1H),3.18(m,2H),2.75(m,2H);ESIMS m/z 419.14([M+H]-);IR(薄膜)1708.94,1113.60,807.77cm-1。
以下化合物根據實例21中揭示之程序製造。
(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2,3-二氫-1H-茚-1-酮(BI4)
產物以棕色半固體狀分離(1.2g,16%):1H NMR(400MHz,CDCl3)δ 7.76(d,J=7.4Hz,1H),7.54(m,3H),7.30(s,1H),6.68(d,J=7.4Hz,1H),6.52(m,1H),4.18(m,1H),3.18(m,2H),2.75(m,2H);ESIMS m/z 400.84([M-H]-);IR(薄膜)815,1113,1709cm-1。
(E)-6-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-3,4-二氫萘-1(2H)-酮(BI5)
產物以淺黃色半固體狀分離(1.2g,30%):1H NMR(400MHz,CDCl3)δ 8.20(d,J=8.0Hz,1H),7.42(s,2H),7.35(m,1H),7.24(m,2H),6.62(d,J=16Hz,1H),6.46(m,1H),4.18(m,1H),2.95(m,2H),2.65(m,2H),2.19(m,2H);ESIMS m/z 432.94([M-H]-);IR(薄膜)1680,1113,808
cm-1。
向經攪拌之(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2,3-二氫-1H-茚-1-酮(0.5g,1.24mmol)於MeCN(20mL)中之溶液中添加Selectfluor®(0.52g,1.48mmol),且將反應物加熱至回流溫度後持續16h。將反應混合物冷卻至室溫,在減壓下濃縮且用CH2Cl2稀釋。溶液用水及鹽水洗滌,經無水Na2SO4乾燥且在減壓下濃縮,得到粗產物,該粗產物藉由急驟管柱層析(SiO2,100-200篩目;配於石油醚之15% EtOAc)純化,得到呈淺黃色半固體狀之標題化合物(0.1g,24%):1H NMR(400MHz,CDCl3)δ 7.80(m,1H),7.48(m,2H),7.32(m,2H),6.65(d,J=16.0Hz,1H),6.54(dd,J=16.0,8.0Hz,1H),5.38(m,1H),4.18(m,1H),3.62(m,1H),3.32(m,1H);ESIMS m/z 419.06([M-H]-);IR(薄膜)1728,1114,817cm-1。
在冷卻時向經攪拌之(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2,3-二氫-1H-茚-1-酮(0.15g,0.35mmol)於DCE(10mL)中之溶液中添加三氟丙胺(0.048g,0.42mmol)及NaBH3CN(0.055g,0.875mmol),且將反應混合物在室溫下攪拌16h。反應混合物用DCE稀釋,用水及鹽水洗滌且經無水Na2SO4乾燥。在減壓下濃縮,得到粗化合物,該粗化合物藉由急驟管柱層析(SiO2,100-200篩目;配於石油醚之10-15% EtOAc)純化,得到呈無色膠狀物質之標題化合物(0.042g,24%):1H NMR(400MHz,CDCl3)δ 7.38-7.20(m,5H),6.62(d,J=16.0Hz,1H),6.34(dd,J=16.0,8.0Hz,1H),5.83(br,1H),5.52(m,1H),4.12(m,1H),3.02(m,3H),2.82(m,1H),2.50(m,2H),1.82(m,1H),1.42(m,1H);ESIMS m/z 497.98([M-H]-);IR(薄膜)3027,1654,815cm-1。
向經攪拌之((E)-6-(4,4,4-三氟-3-(3,4,5-三氯苯基)
丁-1-烯基)-3,4-二氫萘-1(2H)-酮(0.4g,0.92mmol)於EtOH(50mL)中之溶液中添加羥胺鹽酸鹽(0.128g,1.85mmol)及乙酸鈉(NaOAc,0.23g,2.77mmol),且將反應混合物在回流下加熱3h。在減壓下濃縮反應混合物,且殘餘物用水稀釋且用EtOAc萃取。合併之有機萃取物用鹽水洗滌,經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物,該粗化合物藉由急驟管柱層析(SiO2,100-200篩目;配於石油醚之10-15% EtOAc)純化。標題化合物以固體狀分離(0.3g,73%):mp 155-158℃;1H NMR(400MHz,CDCl3)δ 7.89(d,J=8.4Hz,1H),7.41(s,2H),7.24(m,1H),7.17(m,1H),6.57(d,J=16Hz,1H),6.46(dd,J=16.0,8.0Hz,1H),4.13(m,1H),2.82(m,4H),2.04(m,2H);ESIMS m/z 445.95([M-H]-)。
向經攪拌之(E)-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2,3-二氫-1H-茚-1-酮(1g,2.39mmol)於MeOH(10mL)中之溶液中添加乙酸銨(NH4OAc,1.84g,23.9mmol)及NaBH3CN(0.44g,7.17mmol),且將反應混合物在回流下加熱16h。在減壓下濃縮反應混合物,且殘餘物用水稀釋且用EtOAc萃取。合併之有機萃取物用水及NaHCO3
飽和水溶液洗滌,經無水Na2SO4乾燥,且在減壓下濃縮,得到呈液體狀之標題化合物(500mg,粗物質):1H NMR(400MHz,DMSO-d 6)δ 7.85(s,2H),7.40(s,1H),7.30(s,2H),6.71(s,2H),4.78(m,1H),4.2(m,1H),2.80(m,1H),2.73(m,1H),1.60(m,2H);ESIMS m/z 419.02([M+H]+);IR(薄膜)2924,1552,1112,807cm-1。
以下化合物根據實例25中揭示之程序製造。
(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2,3-二氫-1H-茚-1-胺(BI7)
產物以淡棕色膠狀物質分離,原樣用於下一步驟(0.15g,粗化合物):ESIMS m/z 401.97([M-H]-)。
(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-2-氟-2,3-二氫-1H-茚-1-胺(BI8)
產物以淡棕色膠狀物質分離,原樣用於下一步驟(0.15g,粗化合物):ESIMS m/z 420.15([M-H]-)。
(E)-6-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-1,2,3,4-四氫萘-1-胺(BI9)
產物以淺黃色液體狀分離(500mg粗物質)。
向經攪拌之(E)-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2,3-二氫-1H-茚-1-胺(0.1g,0.23mmol)於Et2O(5mL)中之溶液中添加異硫氰酸甲酯(0.026g,0.35mmol),且將混合物在25℃下攪拌2h。在減壓下濃縮反應混合物,且殘餘物藉由急驟管柱層析(SiO2,配於石油醚之20% EtOAc)純化。標題化合物以液體狀分離(65mg,50%):1H NMR(400MHz,CDCl3)δ 7.39(s,2H),7.25-7.18(m,3H),6.58(d,J=16.0Hz,1H),6.30(dd,J=16.0,8.4Hz,1H),5.91-5.70(br,2H),4.05(m,1H),3.05-2.80(m,6H),2.70(m,1H),1.81(m,1H);ESIMS m/z 492.17([M+H]+);IR(薄膜)3211,1569,1113,806cm-1。
表1中之化合物BC2-BC3根據實例26中揭示之程序製造。
向經攪拌之(E)-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2,3-二氫-1H-茚-1-胺(0.1g,0.23mmol)於CH2Cl2(10mL)中之溶液中添加三氟丙酸(0.044g,0.34mmol)、EDC.HCl(0.038g,0.35mmol)、HOBt.H2O(0.07g,0.46mmol)及DIPEA(0.074g,0.57mmol),且將反應混合物在25℃下攪拌16h。反應混合物用CH2Cl2稀釋且用水洗滌。合併之有機層用鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮。粗物質藉由急驟管柱層析(SiO2,配於石油醚之15% EtOAc)純化,得到呈液體狀之標題化合物(65mg,65%):1H NMR(400MHz,CDCl3)δ 7.39(s,2H),7.25-7.20(m,3H),6.34(d,J=16.0Hz,1H),6.30(dd,J=16.0,8.0Hz,1H),5.81(br,1H),5.48(m,1H),4.10(m,1H),3.10(m,2H),2.86-3.07(m,2H),2.86(m,1H),1.81(m,1H);ESIMS m/z 529.02([M+H]+);IR(薄膜)3283,1652,1241,811cm-1。
表1中之化合物BC5-BC9、BC11根據實例27中揭示之程序製造。
步驟1. 5-溴-吲哚啉(BI11):經20min之時間在10℃下向含5-溴-1H-吲哚(2.5g,12.82mmol)之AcOH(10.0mL)中逐份添加NaBH3CN(2.38g,38.46mmol)。此後,將反應混合物在環境溫度下攪拌3h。反應混合物用水稀釋且用Et2O萃取。有機層用飽和NaHCO3、水及鹽水溶液洗滌。合併之醚層經無水Na2SO4乾燥且在減壓下濃縮,得到呈淺黃色半固體狀之標題化合物(1.8g,71%)。
步驟2. 第三丁基-5-溴吲哚啉-1-甲酸酯(BI12):向經攪拌之5-溴-吲哚啉(3.0g,15mmol)於MeCN(100mL)中之溶液中添加DMAP(0.185g,1.522mmol)及二碳酸二第三丁酯(3.98g,18.3mmol),且將反應物在環境溫度下攪拌16h。在減壓下濃縮反應混合物,獲得殘餘物,該殘餘物用Et2O稀釋且用水及鹽水溶液洗滌(2×)。合併之醚層經無水Na2SO4乾燥且在減壓下濃縮,得到呈灰白色固體狀之粗產物(3.0g),該粗產物未經進一步純化即用於下一步驟。
步驟3. 第三丁基-5-乙烯基吲哚啉-1-甲酸酯(BI10):將經攪拌之第三丁基-5-溴吲哚啉-1-甲酸酯(2.0g,6.73mmol)、乙烯基三氟硼酸鉀(2.6g,20.20mmol)及K2CO3(2.78g,20.2mmol)於DMSO(50.0mL)中之溶液在環境溫度下用氬氣脫氣20min。在環境溫度下添加PdCl2(dppf)(0.49g,0.67mmol),接著將反應混合物加熱至100℃後持續3h。將反應混合物冷卻至環境溫度且經由Celite®床在真空下過濾且用Et2O洗滌。反應混合物用Et2O萃取。合併之Et2O層經Na2SO4乾燥且在減壓下濃縮,得到
粗產物。粗化合物藉由管柱層析(SiO2,100-200篩目;用配於石油醚之2% EtOAc溶離)純化,得到呈灰白色固體狀之標題化合物(1.2g,73%):mp 85.5-88.6℃;1H NMR(400MHz,CDCl3)δ 7.23(m,3H),6.69(dd,J=17.4,10.8Hz,1H),5.64(d,J=10.5Hz,1H),5.13(d,J=10.5Hz,1H),4.00(t,J=9.0Hz,2H),3.10(t,J=9.0Hz,2H),1.55(bs,9H)。
向經攪拌之第三丁基-5-乙烯基吲哚啉-1-甲酸酯(1.28g,5.23mmol)於1,2-二氯苯(10.0mL)中之溶液中添加5-(1-溴-2,2,2-三氟乙基)-1,3-二氯-2-氟苯(3.4g,10mmol)、CuCl(103mg,1.05mmol)及2,2-聯吡啶(0.326g,2.092mmol),且所得反應混合物用氬氣脫氣30min且加熱至150℃後持續1h。將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之2% EtOAc)純化,得到呈淺黃色膠狀固體狀之標題化合物(0.3g,61%):1H NMR(400MHz,CDCl3)δ 7.34(d,J=6.0Hz,2H),7.22(s,2H),7.16(d,J=8.4Hz,1H),6.52(d,J=16.0Hz,1H),6.21(dd,J=16.0,7.6Hz,1H),4.07(m,3H),3.10(t,J=8.4Hz,2H),1.55(s,9H);ESIMS m/z 433.79([M-H]-);IR(薄膜)1168,858cm-1。
步驟1. (E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)吲哚啉(BI15)向經攪拌之(E)-第三丁基-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)吲哚啉-1-甲酸酯(0.2g,0.4mmol)於CH2Cl2(10.0mL)中之溶液中添加TFA(0.6mL),且將反應物在環境溫度下攪拌2h。反應混合物用CH2Cl2稀釋,用NaHCO3飽和水溶液、水及鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到呈淡棕色膠狀物質之粗產物(0.12g),該粗產物未經進一步純化即用於下一步驟:1H NMR(400MHz,CDCl3)δ 7.33(d,J=6.4Hz,2H),7.21(s,1H),7.02(d,J=8.0Hz,1H),6.57(d,J=8.4Hz,1H),6.49(d,J=15.6Hz,1H),6.21(dd,J=15.6,8.4Hz,1H),4.07(m,1H),3.61(t,J=8.4Hz,2H),3.05(t,J=8.4Hz,2H);ESIMS m/z 389.89([M+H]+);IR(薄膜)3385,1112,816cm-1。
步驟2. 5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1-亞硝基吲哚啉(BI16):在5℃下向含(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)吲哚啉(0.2g,0.5mmol)之濃HCl(5.0mL)中緩慢添加含NaNO2之水,且在環境溫度下攪拌反應物2h。反應混合物用CH2Cl2稀釋,且CH2Cl2層
用水及鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到呈淺黃色固體狀之粗產物,該粗產物未經進一步純化即用於下一步驟(0.2g):1H NMR(400MHz,CDCl3)δ 7.33(d,J=8.4Hz,1H),7.39(m,4H),6.61(d,J=16.0Hz,1H),6.35(dd,J=16.0,8.4Hz,1H),4.07(m,3H),3.23(t,J=8.4Hz,2H);ESIMS m/z 418.82([M+H]+);IR(薄膜)1488,1112,860cm-1。
步驟3. (E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)吲哚啉-1-胺(BI14):向含(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1-亞硝基吲哚啉(0.1g,0.2mmol)之MeOH(10.0mL)中添加含鋅粉(77.5mg)及NH4Cl(36.9mg,0.69mmol)之水(2.0mL)。將反應混合物在環境溫度下攪拌3h。反應混合物用CH2Cl2稀釋,且CH2Cl2層用水及鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物,該粗化合物藉由管柱層析(SiO2,100-200篩目;用配於石油醚之2% EtOAc溶離)純化,得到呈淡棕色膠狀物質之標題化合物(0.08g):ESIMS m/z 404.86([M+H]+)。
向經攪拌之(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)吲哚啉-1-胺(0.1g,0.247mmol)於CH2Cl2(10.0mL)中之溶液中添加3,3,3-三氟丙酸(0.038g,0.297mmol)、PyBOP(0.192g,0.370mmol)及DIPEA(0.047g,0.370mmol),且將反應物在環境溫度下攪拌18h。反應混合物用CH2Cl2稀釋,且分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之20-25% EtOAc)純化,得到呈淡棕色膠狀物質之標題化合物(0.12g,33%):1H NMR(400MHz,CDCl3)δ 7.32,(d,J=6.0Hz,2H)7.28(m,1H),7.20(d,J=8.0,1H),7.14(d,J=8.8,1H),6.70(d,J=8.0Hz,1H),6.60(m,2H),4.15(m,1H),3.85(m,1H),3.65(m,1H),3.46(m,2H),3.19(m,2H);ESIMS m/z 514.86([M+H]+);IR(薄膜)3428,1112,857cm-1。
步驟1. 5-乙烯基-1H-吲哚(BI18):5-溴-1H-吲哚(2.5g,12.82mmol)、乙烯基三氟硼酸鉀(2.57g,19.2mmol)、Cs2CO3(12.53g,38.46mmol)及三苯基膦(201mg,0.769mmol)於THF/水(9:1,75ml)中之混合物用氬氣脫氣20min,接著以PdCl2(45.3mg,0.256mmol)饋入。將反應混合
物加熱至回流後持續16h,接著冷卻至環境溫度,經由Celite®床過濾且用EtOAc洗滌。再用EtOAc萃取濾液,且合併之有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之2% EtOAc)純化,得到呈淡棕色膠狀物質之標題化合物(1.5g,83%):1H NMR(400MHz,CDCl3)δ 8.20(br,1H),7.68(s,1H),7.45(s,2H),7.21(m,1H),6.90(dd,J=16.0,10.8Hz,1H),6.55(m,1H),5.75(d,J=10.5Hz,1H),5.21(d,J=10.5Hz,1H);ESIMS m/z 142.05([M-H]-)。
步驟2. 第三丁基-5-乙烯基-1H-吲哚-1-甲酸酯(BI17):向經攪拌之5-乙烯基-1H-吲哚(0.7g,4.89mmol)於MeCN(20ml)中之溶液中添加DMAP(59.65mg,0.489mmol)及二碳酸二第三丁酯(1.38g,6.36mmol),且將反應物在環境溫度下攪拌3h。在減壓下濃縮反應混合物,獲得殘餘物,該殘餘物用CH2Cl2稀釋且用水及鹽水溶液洗滌。合併之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之2% EtOAc)純化,得到呈灰白色半固體狀之標題化合物(0.7g,59%):1H NMR(400MHz,CDCl3)δ 8.15(d,J=8.0Hz,1H),7.60(s,2H),7.30(d,J=8.4Hz,1H),7.21(m,1H),6.90(dd,J=16.0,10.8Hz,1H),6.59(s,1H),5.75(d,J=10.5Hz,1H),5.21(d,J=10.5Hz,1H),1.65(s,9H);ESIMS m/z 242.10([M-H]-);IR(薄膜)1630cm-1。
向經攪拌之5-乙烯基-1H-吲哚-1-甲酸第三丁酯(0.65g,2.67mmol)於1,2-二氯苯(10.0mL)中之溶液中添加5-(1-溴-2,2,2-三氟乙基)-1,3-二氯-2-氟苯(1.74g,5.37mmol)、CuCl(53mg,0.537mmol)及2,2-聯吡啶(167mg,1.07mmol)。所得反應混合物用氬氣脫氣30min且將其加熱至150℃後持續2h。將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之2% EtOAc)純化,得到呈淡棕色膠狀物質之標題化合物(0.25g,10%):1H NMR(400MHz,CDCl3)δ 8.20(d,J=8.0Hz,1H),7.60(m,2H),7.39(m,3H),6.69(d,J=16.0Hz,1H),6.55(d,J=10.5Hz,1H),6.36(dd,J=16.0,8.0Hz,1H),4.10(m,1H),1.65(s,9H);ESIMS m/z 485.91([M-H]-);IR(薄膜)1165,854cm-1。
向經攪拌之(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1H-吲哚-1-甲酸第三丁酯(0.2g,0.40mmol)
於CH2Cl2(10.0mL)中之溶液中添加TFA(70mg,0.61mmol),且將反應物在環境溫度下攪拌2h。反應混合物用CH2Cl2稀釋且用NaHCO3飽和溶液、水及鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到呈淡棕色固體狀之標題化合物(0.2g,97%):mp 132.9-138.8℃;1H NMR(400MHz,CDCl3)δ 11.19(br,1H),8.20(d,J=8.0Hz,1H),7.60(m,2H),7.39(m,3H),6.69(d,J=16.0Hz,1H),6.55(d,J=10.5Hz,1H),6.36(dd,J=16.0,8.0Hz,1H),4.82(m,1H);ESIMS m/z 387.98([M+H]+)。
向經攪拌之4-硝基苯酚(1.0g,7.19mmol)於CH2Cl2(20.0mL)中之溶液中添加N-Boc甘胺酸(1.38g,7.91mmol)及EDC HCl(2.05g,10.785mmol),且將反應物在環境溫度下攪拌24h。反應混合物用CH2Cl2稀釋且用水及飽和鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到呈淡棕色膠狀物質之標題化合物(1.1g),該標題化合物未經進一步純化即用於下一步驟:1H NMR(400MHz,CDCl3)δ 8.29(d,J=9.2Hz,2H),7.33(d,J=8.8Hz,2H),5.07(br,1H),4.20(s,2H),1.47(s,9H);ESIMS m/z 296.27([M+H]+)。
向經攪拌之(E)-5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1H-吲哚(0.1g,0.258mmol)於MeCN(5.0mL)中之溶液中添加2-(第三丁氧基羰基胺基)乙酸4-硝基苯酯(0.114g,0.387mmol)、KF(0.03g,0.516mmol)、18-冠-6-醚(0.075g,0.283mmol)及DIPEA(0.0332g,0.258mmol),且將反應物在環境溫度下攪拌16h。濃縮反應混合物以獲得殘餘物,該殘餘物用CH2Cl2稀釋且用水及鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到呈淡棕色膠狀物質之粗標題化合物(0.1g),該粗標題化合物未經進一步純化即用於下一步驟:ESIMS m/z 545.23([M+H]+)。
步驟1. (E)-2-胺基-1-(5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1H-吲哚-1-基)乙酮(BI23):向經攪拌
之(E)-2-(5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1H-吲哚-1-基)-2-側氧基乙基胺基甲酸第三丁酯(0.05g,0.09mmol)於CH2Cl2(5.0mL)中之溶液中添加TFA(0.01mL),且將反應物在環境溫度下攪拌16h。反應混合物用CH2Cl2稀釋且用NaHCO3飽和溶液、水及鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗標題化合物(50mg),該粗標題化合物未經進一步純化即用於下一步驟。
步驟2. (E)-N-(2-(5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)-1H-吲哚-1-基)-2-側氧基乙基)-3,3,3-三氟丙醯胺(BC13):向經攪拌之(E)-2-胺基-1-(5-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1H-吲哚-1-基)乙酮(0.04g,0.09mmol)於CH2Cl2(5.0mL)中之溶液中添加3,3,3-三氟丙酸(17.5mg,0.136mmol)、PyBOP(70mg,0.135mmol)及DIPEA(29mg,0.225mmol),且將反應物在環境溫度下攪拌16h。反應混合物用CH2Cl2稀釋,且CH2Cl2層用水及飽和鹽水溶液洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物,該粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之10% EtOAc)純化,得到呈灰白色固體狀之標題化合物(30mg,60%):mp 121-126℃;1H NMR(400MHz,CDCl3)δ 8.33(br,1H),7.59(s,1H),7.45(m,4H),6.72(d,J=3.6Hz,3H),6.39(m,1H),4.71(t,J=7.2Hz,2H),4.15(m,1H),3.51(m,1H),3.28(m,1H);ESIMS m/z 553.06([M-H]-)。
步驟1. 5-溴-3-羥基異吲哚啉-1-酮(BI25):將Zn粉(1.73g,26.154mmol)、五水合硫酸銅(II)(0.02g,0.08mmol)及2M NaOH水溶液(27mL)之混合物冷卻至0℃。在相同溫度下經30min之時間添加5-溴異吲哚啉-1,3-二酮(5g,22mmol)。將反應混合物在0℃下攪拌30min且在環境溫度下攪拌3h。過濾反應混合物,且用濃HCl中和濾液。反應混合物用乙醇稀釋且用EtOAc萃取。合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,得到呈棕色固體狀之粗標題化合物(1.3g),該粗標題化合物未經進一步純化即用於下一步驟:mp 258-261℃;1H NMR(400MHz,DMSO-d 6)δ 9.03(br,1H),7.81(m,2H),7.69(m,1H),6.44(m,1H),5.88(d,J=9.3Hz,1H);ESIMS m/z 225.83([M-H]-);IR(薄膜)1684,3246,606cm-1。
步驟2. 6-溴酞嗪-1(2H)-酮(BI26):向經攪拌之5-溴-3-羥基異吲哚啉-1-酮(1.0g,4.40mmol)於水中之溶液中添加水合肼(0.45g,8.80mmol)且加熱至95℃後持續5h。將反應混合物冷卻至環境溫度,過濾且用Et2O及戊烷(1:1)洗滌,得到呈白色固體狀之標題化合物(0.5g),該標題化合物未經進一步純化即用於下一步驟:ESIMS m/z 225.15([M+H]+)。
步驟3. 6-乙烯基酞嗪-1(2H)-酮(BI27):6-溴酞嗪-1(2H)-酮(0.25g,1.11mmol)、乙烯基三氟硼酸鉀(0.446g,3.33mmol)及K2CO3(0.46g,3.33mmol)於DMSO(2mL)中之溶液在環境溫度下用氬氣脫氣20min。在環境溫度下添加PdCl2(dppf)(0.04g,0.055mmol),且將反應混合物加熱至80℃後持續2h。將反應混合物冷卻至環境溫度,且經由Celite®床在真空下過濾且用EtOAc洗滌。反應混合物用EtOAc萃取且合併之EtOAc層經Na2SO4乾燥且在減壓下濃縮,得到粗產物。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之50% EtOAc)純化,得到呈棕色固體狀之標題化合物(0.12g,63%):1H NMR(400MHz,DMSO-d 6)δ 13.61(br,1H),8.33(m,1H),8.19(m,1H),8.01(m,2H),6.97(m,1H),6.15(m,1H),5.56(d,J=10.8Hz,1H);ESIMS m/z 172.93([M+H]+);IR(薄膜)1748,1655,3241cm-1。
步驟4. 乙基-2-(1-側氧基-6-乙烯基酞嗪-2(1H)-基乙酸酯(BI24):向經攪拌之6-乙烯基酞嗪-1(2H)-酮(0.5g,2.90mmol)於DMF(5.0mL)中之溶液中添加Cs2CO3(0.94g,2.90mmol),且將反應物攪拌10min。在環境溫度下將溴乙酸乙酯(0.48g,2.90mmol)添加至反應混合物中,且將反應物在環境溫度下攪拌8h。反應混合物經稀釋且用EtOAc萃取,且EtOAc層用水及鹽水溶液洗滌(2×)。分離之EtOAc層經無水Na2SO4乾燥且在減壓下濃縮,得到粗產物。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之25% EtOAc)純化,得到呈棕色固體狀之標題化合物
(0.34g,45%):1H NMR(400MHz,DMSO-d 6)δ 8.45(m,1H),8.24(m,1H),8.04(m,2H),7.01(m,1H),6.17(d,J=2.1Hz,1H),5.56(d,J=10.8Hz,1H),4.92(s,2H),4.19(m,2H),1.23(m,3H)。ESIMS m/z 259.10([M+H]+);IR(薄膜)1750,1660cm-1。
向經攪拌之乙基-2-(1-側氧基-6-乙烯基酞嗪-2(1H)-基乙酸酯(0.07g,0.27mmol)於1,2-二氯苯(1.0mL)中之溶液中添加5-(1-溴-2,2,2-三氟乙基)-1,3-二氯-2-氟苯(0.17g,0.54mmol)、CuCl(0.005g,0.05mmol)及2,2-聯吡啶(0.016g,0.10mmol),且所得反應混合物用氬氣脫氣30min且將其加熱至180℃後持續12h。將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之10-15% EtOAc)純化,得到呈棕色固體狀之標題化合物(40mg,29%):1H NMR(400MHz,DMSO-d 6)δ 8.40(d,J=8.4Hz,1H),7.84(d,J=1.5Hz,1H),7.65(s,1H),7.37(d,J=6.3Hz,2H),6.76(d,J=16.0Hz,1H),6.59(dd,J=16.0,8.0Hz,1H),4.96(s,2H),4.29(m,3H),1.31(t,J=7.2Hz,3H);ESIMS m/z 503.0([M+H]+);IR(薄膜)1660,1114,817cm-1。
將(E)-乙基-2-(6-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1-側氧基酞嗪-2(1H)-基)乙酸酯(0.04g,0.07mmol)於HCl(0.5mL)及AcOH(0.5mL)中之溶液加熱至100℃後持續3h。在減壓下移除溶劑,且用水稀釋殘餘物。水層用EtOAc萃取,且分離之EtOAc層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物用Et2O-戊烷混合物濕磨,得到呈棕色固體狀之標題化合物(0.03g):1H NMR(400MHz,DMSO-d 6)δ 13.0(br s,1H),8.43(m,1H),8.23(d,J=8.1Hz,1H),8.14(m,2H),7.91(m,2H),7.16(dd,J=16.0,8.0Hz,1H),6.99(d,J=16.0Hz,1H),4.96(m,3H);ESIMS m/z 473.0([M-H]-);IR(薄膜)1629,1168,817cm-1。
在環境溫度下向經攪拌之(E)-2-(6-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-1-側氧基酞嗪-2(1H)-基)
乙酸(0.15g,0.31mmol)於CH2Cl2(20.0mL)中之溶液中添加2,2,2,-三氟乙胺(0.03g,0.31mmol)、PyBOP(0.17g,0.34mmol)及DIPEA(0.15ml,0.93mmol),且將反應物攪拌18h。反應混合物用CH2Cl2稀釋且用3N HCl(2×20mL)、NaHCO3(2×20mL)及鹽水溶液(2×)洗滌。分離之CH2Cl2層經無水Na2SO4乾燥且在減壓下濃縮,得到粗化合物。粗化合物藉由管柱層析(SiO2,100-200篩目;配於石油醚之20-25% EtOAc)純化,得到呈棕色固體狀之標題化合物(0.11g):mp 172-175℃;1H NMR(400MHz,CDCl3)δ 8.83(t,J=6.6Hz,1H),8.42(t,J=14.7Hz,1H),8.22(d,J=8.1Hz,1H),8.13(t,J=6.3Hz,1H),7.98-7.86(m,2H),7.16-7.07(m,1H),7.01-6.93(m,1H),4.96-4.81(m,3H),4.00-3.88(m,2H);ESIMS m/z 554.0([M-H]-)。
向經攪拌之1-(氯甲基)-4-乙烯基苯(10g,66mmol)於DMF(100mL)中之溶液中添加鄰苯二甲醯亞胺鉀(13.3g,72.1mmol),且將所得反應混合物在70℃下加熱16h。反應混合物用水稀釋且用CHCl3萃取。合併之CHCl3層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。自MeOH再結晶,得到呈灰白色固體狀之標題化合物(8g,46%):1H
NMR(400MHz,CDCl3)δ 7.83(m,2H),7.71(m,2H),7.39(m,4H),6.65(dd,J=17.6,10.8Hz,1H),5.72(d,J=17.6Hz,1H),5.21(d,J=10.8Hz,1H),4.82(s,2H);GCMS m/z 263.2([M]+);IR(薄膜)3420,1133,718cm-1。
使用實例10之程序,用2-(4-乙烯基苯甲基)異吲哚啉-1,3-二酮及1-(1-溴乙基)-3,5-二氯苯作為起始物質,標題化合物以灰白色固體狀分離(0.3g,40-50%):mp 142-145℃;1H NMR(400MHz,CDCl3)δ 7.86(m,2H),7.74(m,2H),7.42(m,2H),7.36(m,3H),7.27(m,2H),6.58(d,J=16.0Hz,1H),6.32(dd,J=16.0,8.0Hz,1H),4.82(s,2H),4.05(m,1H);ESIMS m/z 488.17([M-H]-)。
以下化合物根據實例43中揭示之程序製造。
(E)-2-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)異吲哚啉-1,3-二酮(CI3)
標題化合物以灰白色固體狀分離(0.3g,56%):mp 145-146℃;1H NMR(400MHz,CDCl3)δ 7.86(m,2H),
7.74(m,2H),7.42-7.31(m,6H),6.58(d,J=16.0Hz,1H),6.53(dd,J=16.0,8.0Hz,1H),4.82(s,2H),4.05(m,1H);ESIMS m/z 522.2([M-H]-);IR(薄膜)1716,1110,712cm-1。
預示性地,化合物CI4-CI5(表1)可根據實例43中揭示之程序製造。
向經攪拌之(E)-2-(4-(3-(3,5-二氯苯基)丁-1-烯-1-基)苯甲基)-異吲哚啉-1,3-二酮(1.2g,2.45mmol)於EtOH中之溶液中添加水合肼(0.61g,12mmol),且將所得反應混合物在90℃下加熱1h。過濾反應混合物,且濃縮濾液。將殘餘物溶解於CH2Cl2中,用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈膠狀液體狀之粗標題化合物(0.9g),該粗標題化合物未經進一步純化即使用。
以下化合物根據實例44中揭示之程序製造。
(E)-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)甲胺(CI7)
標題化合物經分離且未經進一步純化即使用。
預示性地,化合物CI8-CI9(表1)可根據實例44中揭示之程序製造。
在氬氣氛圍下向經攪拌之3-氯-4-甲基苯甲腈(5g,25.4mmol)於CCl4(50mL)中之溶液中添加NBS(5.16g,29mmol),且將混合物脫氣30min。向此混合物中添加AIBN(0.3g,1.8mmol),且將所得反應混合物在回流下加熱4h。將反應混合物冷卻至環境溫度,用水洗滌,且用CH2Cl2萃取。合併之CH2Cl2層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟管柱層析(SiO2,100-200篩目;配於正己烷之5% EtOAc)純化,得到呈白色固體狀之標題化合物(4.8g,68%):mp 87-88℃;1H NMR(400MHz,CDCl3)δ 7.71(s,1H),7.59(s,2H),4.60(s,2H);ESIMS m/z 229.77([M+H]+);IR(薄膜)2235,752,621cm-1。
以下化合物根據實例45中揭示之程序製造。
4-(溴甲基)-3-(三氟甲基)苯甲腈(CI11)
標題化合物以灰白色膠狀物質分離(5g,66%):
1H NMR(400MHz,CDCl3)δ 7.96(s,1H),7.86(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),4.62(s,2H);ESIMS m/z 262.11([M-H]-);IR(薄膜)2236,1132,617cm-1。
3-溴-4-(溴甲基)苯甲腈(CI12)
標題化合物以灰白色固體狀分離(5g,67%):mp 82-83℃;1H NMR(400MHz,CDCl3)δ 7.90(s,1H),7.61(m,2H),4.62(s,2H);EIMS m/z 272.90;IR(薄膜)2229,618cm-1。
4-(溴甲基)-3-氟苯甲腈(CI13)
標題化合物以灰白色固體狀分離(2g,60%):mp 79-81℃;1H NMR(400MHz,CDCl3)δ 7.54(t,J=8.0Hz,1H),7.48(dd,J=8.0Hz,8.0,1H),7.38(dd,J=5Hz,1H),4.5(s,2H);EIMS m/z 215。
在0℃下向經攪拌之4-(溴甲基)-3-氯苯甲腈(4.8
g,17mmol)於甲苯(50mL)中之溶液中逐滴添加DIBAL-H(1.0M甲苯溶液;23.9mL),且將反應混合物在0℃下攪拌1h。添加含10M HCl之水(5mL)直至反應混合物變成白色漿料,且接著再添加1N HCl(20mL)。收集有機層,且水層用CHCl3萃取。合併之有機層經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟管柱層析(SiO2,100-200篩目;配於正己烷之5% EtOAc)純化,得到呈白色固體狀之標題化合物(3.8g,80%):mp 64-66℃;1H NMR(400MHz,CDCl3)δ 10.00(s,1H),7.92(s,1H),7.78(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),4.60(s,2H);ESIMS m/z 232.78([M+H]+)。
以下化合物根據實例46中揭示之程序製造。
4-(溴甲基)-3-(三氟甲基)苯甲醛(CI15)
標題化合物以淺黃色低熔點固體狀分離(5g,60%):1H NMR(400MHz,CDCl3)δ 10.09(s,1H),8.19(s,1H),8.09(m,1H),7.81(m,1H),4.61(s,2H);ESIMS m/z 265.04([M-H]-);IR(薄膜)1709,1126,649cm-1。
3-溴-4-(溴甲基)苯甲醛(CI16)
標題化合物以淺黃色固體狀分離(5g,62%):mp
94-95℃;1H NMR(400MHz,CDCl3)δ 9.96(s,1H),8.05(s,1H),7.81(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),4.60(s,2H);EIMS m/z 275.90([M]+)。
4-(溴甲基)-3-氟苯甲醛(CI17)
標題化合物以灰白色固體狀分離(5g,61%):mp 43-45℃;1H NMR(400MHz,CDCl3)δ 9.1(s,1H),7.54(t,J=8Hz,1H),7.48(d,J=8Hz,1H),7.38(d,J=5Hz,1H),4.5(s,2H);EIMS m/z 216([M]+)。
向經攪拌之4-(溴甲基)-3-氯苯甲醛(3.8g,14mmol)於DMF(40mL)中之溶液中添加鄰苯二甲醯亞胺鉀(3.54g,19.14mmol),且將混合物在60℃下加熱6h。將反應混合物冷卻至環境溫度且用水(100mL)稀釋。所獲得之固體藉由過濾分離且在真空下乾燥,得到呈白色固體狀之標題化合物(2.8g,60%):mp 123-126℃;1H NMR(400MHz,CDCl3)δ 9.95(s,1H),8.21(s,1H),7.91(m,3H),7.80(m,
2H),7.20(m,1H),5.05(s,2H);ESIMS m/z 298.03([M-H]-)。
以下化合物根據實例47中揭示之程序製造。
4-((1,3-二側氧基異吲哚啉-2-基)-3-(三氟甲基)苯甲醛(CI19)
標題化合物以灰白色固體狀分離(1g,62%):mp 142-143℃;1H NMR(400MHz,CDCl3)δ 10.05(s,1H),8.15(s,1H),7.91(m,2H),7.80(m,3H),7.27(m,1H),5.19(s,2H);ESIMS m/z 332.03([M-H]-)。
3-溴-4-((1,3-二側氧基異吲哚啉-2-基)甲基)苯甲醛(CI20)
標題化合物以灰白色固體狀分離(0.5g,64%):mp 159-161℃;1H NMR(400MHz,CDCl3)δ 9.95(s,1H),8.21(s,1H),7.91(m,3H),7.80(m,2H),7.20(m,1H),5.05(s,2H);ESIMS m/z 314.00([M-CHO]-)。
4-((1,3-二側氧基異吲哚啉-2-基)-3-氟苯甲醛(CI21)
標題化合物以白色固體狀分離(2g,60%):mp 154-156℃;1H NMR(400MHz,CDCl3)δ 9.95(s,1H),7.9(m,2H),7.75(m,2H),7.6(m,2H),7.5(t,J=7.6Hz,1H),5.05(s,2H);EIMS m/z 283.1([M]+)。
在環境溫度下向經攪拌之3-氯-4-((1,3-二側氧基異吲哚啉-2-基)甲基)苯甲醛(2.8g,8.2mmol)於1,4-二噁烷(30mL)中之溶液中添加K2CO3(1.68g,12.24mmol)及溴化甲基三苯基鏻(4.37g,12.24mmol)。接著將所得反應混合物在100℃下加熱18h。在利用TLC認為反應完全之後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮所獲得之濾液。殘餘物藉由急驟層析(SiO2,100-200篩目;配於正己烷之20% EtOAc)純化,得到呈白色固體狀之標題化合物(1.94g,70%):mp 141-143℃;1H NMR(400MHz,CDCl3)δ 7.85(m,2H),7.70(m,2H),7.41(m,1H),7.21(m,2H),
6.71(dd,J=17.6,10.8Hz,1H),5.72(d,J=17.6Hz,1H),5.23(d,J=10.8Hz,1H),4.92(s,2H);ESIMS m/z 298.10([M-H]-)。
以下化合物根據實例48中揭示之程序製造。
2-(2-(三氟甲基)-4-乙烯基苯甲基)異吲哚啉-1,3-二酮(CI23)
標題化合物以淡棕色固體狀分離(0.5g,60%):mp 134-135℃;1H NMR(400MHz,CDCl3)δ 7.92(m,2H),7.80(m,2H),7.71(s,1H),7.46(d,J=8.0Hz,1H),7.16(d,J=8.0Hz,1H),6.65(m,1H),5.80(d,J=17.8Hz,1H),5.19(d,J=10.8Hz,1H),5.09(s,2H);ESIMS m/z 332.10([M+H]+)。
2-(2-溴-4-乙烯基苯甲基)異吲哚啉-1,3-二酮(CI24)
標題化合物以灰白色固體狀分離(0.5g,62%):mp 126-128℃;1H NMR(400MHz,CDCl3)δ 7.92(m,2H),7.79(m,2H),7.62(s,1H),7.21(m,1H),7.16(d,J=8.0Hz,
1H),6.62(m,1H),5.72(d,J=17.8Hz,1H),5.15(d,J=10.8Hz,1H),4.95(s,2H);EIMS m/z 341.10([M]+)。
2-(2-氟-4-乙烯基苯甲基)異吲哚啉-1,3-二酮(CI25)
標題化合物以白色固體狀分離(0.5g,61%):mp 140-142℃;1H NMR(400MHz,CDCl3)δ 7.85(m,2H),7.72(m,2H),7.25(m,1H),7.11(m,2H),6.63(m,1H),5.80(d,J=17.6Hz,1H),5.28(d,J=10.8Hz,1H),4.92(s,2H);EIMS m/z 282.08。
向經攪拌之2-(2-氯-4-乙烯基苯甲基)異吲哚啉-1,3-二酮(2.0g,6.51mmol)於1,2-二氯苯(25mL)中之溶液中添加1-(1-溴-2,2,2-三氟乙基)-3,5-二氯苯(3.48g,11.36mmol)、CuCl(112mg,1.13mmol)及2,2-聯吡啶(0.35g)。所得反應混合物用氬氣脫氣30min,且接著將其在180℃下攪
拌24h。在利用TLC認為反應完全之後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。殘餘物藉由急驟層析(SiO2,100-200篩目;配於正己烷之25-30% EtOAc)純化,得到呈固體狀之標題化合物(1.3g,50%):mp 141-143℃;1H NMR(400MHz,CDCl3)δ 7.92(m,2H),7.79(m,2H),7.42(m,2H),7.24(m,2H),7.20(m,2H),6.54(d,J=16.0Hz,1H),6.34(dd,J=16.0,8.0Hz,1H),5.00(s,2H),4.10(m,1H);ESIMS m/z 524.07([M+H]+)。
以下化合物根據實例49中揭示之程序製造。
(E)-2-(2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)異吲哚啉-1,3-二酮(CI27)
標題化合物以灰白色固體狀分離(0.2g,55%):mp 128-129℃;1H NMR(400MHz,CDCl3)δ 7.92(m,2H),7.79(m,2H),7.42(m,3H),7.22(m,2H),6.52(d,J=16.0Hz,1H),6.32(dd,J=16.0,8.0Hz,1H),5.00(s,2H),4.05(m,1H);ESIMS m/z 557.99([M+H]+)。
(E)-2-(2-氯-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲基)異吲哚啉-1,3-二酮(CI28)
標題化合物以灰白色固體狀分離(0.2g,54%):mp 177-180℃;1H NMR(400MHz,CDCl3)δ 7.90(m,2H),7.77(m,2H),7.42(s,1H),7.32(d,J=8.0Hz,2H),7.21(m,2H),6.52(d,J=16.0Hz,1H),6.32(dd,J=16.0,8.0Hz,1H),5.00(s,2H),4.05(m,1H);ESIMS m/z 540.08([M-H]-);IR(薄膜)1716cm-1。
(E)-2-(2-氯-4-(3-(3,4-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲基)異吲哚啉-1,3-二酮(CI29)
標題化合物以灰白色固體狀分離(0.2g,59%):1H NMR(400MHz,CDCl3)δ 7.89(m,2H),7.76(m,2H),7.47(m,3H),7.21(m,3H),6.50(d,J=16.0Hz,1H),6.32(dd,J=16.0,7.6Hz,1H),4.97(s,2H),4.11(m,1H);ESIMS m/z 522.27([M-H]-);IR(薄膜)3064,1717,1111,715cm-1。
(E)-2-(4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-
基)-2-(三氟甲基)-苯甲基)異吲哚啉-1,3-二酮(CI30)
標題化合物以灰白色固體狀分離(0.2g,54%):mp 141-142℃;1H NMR(400MHz,CDCl3)7.94(m,2H),7.80(m,2H),7.69(s,1H),7.44(m,1H),7.38(m,1H),7.24(m,2H),7.19(m,1H),6.60(d,J=16.0Hz,1H),6.39(dd,J=16.0,7.6Hz,1H),5.10(s,2H),4.11(m,1H);ESIMS m/z 556.00([M-H]-)。
(E)-2-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)-苯甲基)異吲哚啉-1,3-二酮(CI31)
標題化合物以灰白色固體狀分離(0.2g,56%):mp 130-132℃;1H NMR(400MHz,CDCl3)δ 7.94(m,2H),7.80(m,2H),7.69(s,1H),7.44(m,3H),7.19(m,1H),6.61(d,J=16.0Hz,1H),6.38(dd,J=16.0,7.6Hz,1H),5.10(s,2H),4.12(m,1H);ESIMS m/z 589.57([M-2H]-)。
(E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)-異吲哚啉-1,3-二酮(CI32)
標題化合物以淺黃色固體狀分離(0.2g,55%):mp 160-162℃;1H NMR(400MHz,CDCl3)δ 7.92(m,2H),7.80(m,2H),7.62(s,1H),7.39(s,2H),7.24(m,1H),7.16(m,1H),6.52(d,J=16.0Hz,1H),6.32(dd,J=16.0,8.0Hz,1H),4.98(s,2H),4.12(m,1H);ESIMS m/z 599.78([M-H]-)。
(E)-2-(2-氟-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)-異吲哚啉-1,3-二酮(CI33)
標題化合物以灰白色固體狀分離(0.2g,55%):mp 72-74℃;1H NMR(400MHz,CDCl3)δ 7.88(m,2H),7.74(m,2H),7.38(s,2H),7.34(m,1H),7.18(m,2H),6.54(d,J=16.0Hz,1H),6.32(dd,J=16.0,8.0Hz,1H),4.91(s,2H),4.08(m,1H);ESIMS m/z 539.89([M-H]-);IR(薄膜)1773
cm-1。
預示性地,化合物CI34-CI41(表1)可根據實例49中揭示之程序製造。
向經攪拌之(E)-2-(2-氯-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯甲基)異吲哚啉-1,3-二酮(0.4g,0.76mmol)於EtOH中之溶液中添加水合肼(0.38g,7.6mmol),且將所得反應混合物在80℃下加熱2h。過濾反應混合物,且濃縮濾液。將殘餘物溶解於CH2Cl2中,用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈膠狀液體狀之標題化合物(0.3g),該標題化合物未經進一步純化即用於下一步驟。
以下化合物根據實例50中揭示之程序製造。
(E)-(2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)-甲胺(CI43)
此反應中所獲得之產物未經進一步純化即用於下一步驟。
(E)-(2-氯-4-(3-(3,4-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)-甲胺(CI44)
此反應中所獲得之產物未經進一步純化即用於下一步驟:1H NMR(400MHz,CDCl3)δ 7.48(d,J=8.4Hz,2H),7.39(m,2H),7.23(m,2H),6.52(d,J=16.0Hz,1H),6.38(dd,J=16.0,7.6Hz,1H),4.12(m,1H),3.90(s,2H);ESIMS m/z 391.90([M-H]-);IR(薄膜)3370,3280,1111,817cm-1。
(E)-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)-苯基)甲胺(CI45)
標題化合物以膠狀物質分離。此反應中所獲得之產物未經進一步純化即用於下一步驟。
(E)-(2-溴-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)-甲胺(CI46)
標題化合物以膠狀物質分離:此反應中所獲得之產物未經進一步純化即用於下一步驟。
(E)-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)-甲胺(CI47)
標題化合物以膠狀物質分離。此反應中所獲得之產物未經進一步純化即用於下一步驟。
(E)-(2-氟-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)-甲胺(CI48)
標題化合物以膠狀物質分離:1H NMR(400MHz,CDCl3)δ 7.40(s,2H),7.33(t,J=7.6Hz,1H),7.13(m,2H),6.56(d,J=16.0Hz,1H),6.33(dd,J=16.0,7.6Hz,1H),4.08(m,1H),3.90(s,2H);ESIMS m/z 413.84([M+H]+);IR(薄膜)3368,3274,1114,808cm-1。
預示性地,化合物CI49-CI57(表1)可根據實例50中揭示之程序製造。
向經攪拌之4-(溴甲基)-3-氯苯甲醛(2g,9mmol)於N,N-二甲基乙醯胺(DMA;20mL)中之溶液中添加K2CO3(2.36g,17.16mmol)及2-胺基吡啶(0.84g,8.58mmol),且將反應混合物在環境溫度下攪拌4h。反應混合物用水稀釋且用EtOAc萃取。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。殘餘物藉由急驟管柱層析(SiO2,100-200篩目;配於正己烷之20% EtOAc)純化,得到呈灰白色固體狀之標題化合物(1.05g,50%):mp 122-123℃;1H NMR(400MHz,CDCl3)δ 9.94(s,1H),8.11(s,1H),7.88(s,1H),7.72(d,J=4.8Hz,1H),7.62(d,J=5.7Hz,1H),7.4(m,1H),6.64(d,J=3.9Hz,1H),6.38(d,J=6.3Hz,1H),5.04(br s,1H),4.71(s,2H);ESIMS m/z 246.97([M+H]+)。
在環境溫度下向經攪拌之3-氯-4-((吡啶-2-基胺基)甲基)苯甲醛(1g,4mmol)於1,4-二噁烷(20mL)中之溶液中添加K2CO3(0.84g,6.09mmol)及溴化甲基三苯基鏻(2.17g,6.09mmol)。接著將所得反應混合物在100℃下加熱18h。在利用TLC認為反應完全之後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮所獲得之濾液。殘餘物藉由急驟層析(SiO2,100-200篩目;配於正己烷之10% EtOAc)
純化,得到呈白色固體狀之標題化合物(0.5g,50%):mp 119-121℃;1H NMR(400MHz,CDCl3)δ 8.12(s,1H),7.42-7.40(m,3H),7.26(s,1H),6.66(m,2H),6.36(d,J=6.3Hz,1H),5.75(d,J=13.2Hz,1H),4.92(br s,1H),4.60(s,2H);ESIMS m/z 245.05([M+H]+)。
在0℃下將2-(二苯基亞甲基胺基)乙酸乙酯(10.2g,38.2mmol)添加至含氫化鈉(NaH;3.18g,133.52mmol)之DMF(50mL)中,且將混合物攪拌30min。向此混合物中添加5-溴-2,3-二氯吡啶(12.9g,57.23mmol),且將反應混合物在環境溫度下攪拌3h。反應混合物用2N HCl溶液淬滅且接著在環境溫度下攪拌4h。混合物用EtOAc萃取。合併之EtOAc層用鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮。藉由急驟管柱層析(配於己烷之20-30% EtOAc)進行純化,得到呈液體狀之標題化合物(1.3g,20%):1H NMR(400MHz,CDCl3)δ 8.52(s,1H),7.89(s,1H),5.09(s1H),4.23(m,2H),2.27(br s,2H),1.26(m,3H);ESIMS m/z 293.05([M+H]+);IR(薄膜)3381,3306,1742,759,523cm-1。
將經攪拌之2-胺基-2-(5-溴-3-氯吡啶-2-基)乙酸乙酯(0.5g,1.7mmol)於3N HCl(25mL)中之溶液在回流下加熱4小時。反應混合物用Et2O及水洗滌。合併之醚層在減壓下濃縮,得到呈灰白色固體狀之標題化合物(400mg,65%):1H NMR(400MHz,CDCl3)δ 8.78(s,1H),8.70(br s,2H),8.45(s,1H),4.56(m,2H);ESIMS m/z 221.15([M+H]+)。
向經攪拌之(5-溴-3-氯吡啶-2-基)甲胺鹽酸鹽(0.3g,1.4mmol)於甲苯(40mL)中之溶液中添加TEA(0.41g,4.08mmol)及鄰苯二甲酸酐(0.24g,1.63mmol),且將反應混合物在回流下加熱2h。在減壓下濃縮反應混合物,且殘餘物用水稀釋且用EtOAc萃取。合併之EtOAc層用鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮。殘餘物藉由管柱層析(配於己烷之20-30% EtOAc)純化,得到呈白色固體狀之標題化合物(0.25g,65%):1H NMR(400MHz,CDCl3)δ 8.78(s,1H),8.45(s,1H),7.88(m,2H),7.74(m,2H),4.56
(m,2H);ESIMS m/z 349([M-H]-);IR(薄膜)3307,1665,1114,813cm-1。
向經攪拌之2-((5-溴-3-氯吡啶-2-基)甲基)異吲哚啉-1,3-二酮(0.23g,0.65mmol)於甲苯(10mL)中之溶液中添加Pd(PPh3)4(3.7mg,0.003mmol)、K2CO3(0.269g,1.95mmol)及乙烯基酸酐吡啶複合物(0.78g,3.28mmol),且將反應混合物在回流下加熱16h。過濾反應混合物,且濾液用水及鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮。藉由急驟管柱層析(配於己烷之20-30% EtOAc)進行純化,得到呈灰白色固體狀之標題化合物(0.2g,65%):1H NMR(400MHz,CDCl3)δ 8.30(s,1H),7.91(m,2H),7.77(m,3H),7.72(m,1H),6.63(m,1H),5.79(d,J=16.0Hz,1H),5.39(d,J=16.0Hz,1H),5.12(s,2H);ESIMS m/z 299.20([M+H]+)。
向經攪拌之2-((3-氯-5-乙烯基吡啶-2-基)甲基)異吲哚啉-1,3-二酮(0.35g,1.17mmol)於1,2-二氯苯(10mL)中之溶液中添加5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(0.8g,2.3mmol)、CuCl(23mg,0.12mmol)、2,2-聯吡啶(0.073g,0.234mmol),且將反應混合物在180℃下加熱16h。反應混合物在減壓下濃縮且藉由管柱層析(配於己烷之20-30% EtOAc)純化,得到呈液體狀之標題化合物(0.4g,50%):mp 79-82℃;1H NMR(400MHz,CDCl3)δ 8.27(s,1H),7.91(m,2H),7.77(m,3H),7.36(s,2H),6.51(d,J=15.6Hz,1H),6.32(dd,J=15.6,8.0Hz,1H),5.30(s,2H),4.13(m,1H);ESIMS m/z 559([M+H]+)。
向經攪拌之(E)-2-((3-氯-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)吡啶-2-基)甲基)異吲哚啉-1,3-二酮(200mg,0.358mmol)於EtOH(5mL)中之溶液中添加水合肼(89.6mg,1.79mmol),且將反應混合物在回流下加熱2h。
在減壓下濃縮反應混合物,且將殘餘物溶解於CH2Cl2中。有機層用水及鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮,得到呈固體狀之標題化合物(100mg)。此反應中所獲得之產物未經進一步純化即用於下一步驟。
在氬氣氛圍下向經攪拌之4-甲基-1-萘甲腈(5g,30mmol)於CCl4(50mL)中之溶液中添加NBS(6.06g,34.09mmol),且將反應混合物脫氣30min。添加AIBN(0.3g,2.1mmol),且將所得反應混合物在回流下加熱4h。將反應混合物冷卻至環境溫度,用水稀釋且用CH2Cl2(3×100mL)萃取。合併之CH2Cl2層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。殘餘物藉由急驟管柱層析(SiO2,100-200篩目;配於正己烷之5% EtOAc)純化,得到呈白色固體狀之標題化合物(3.8g,52%):mp 131-133℃;1H NMR(400MHz,CDCl3)δ 8.33(m,1H),8.24(m,1H),7.88(d,J=8.0Hz,1H),7.78(m,2H),7.62(d,J=8.0Hz,1H),4.95(s,2H);ESIMS m/z 245.92([M+H]+);IR(薄膜)2217cm-1。
在0℃下向經攪拌之4-(溴甲基)-1-萘甲腈(8g,33mmol)於甲苯(100mL)中之溶液中逐滴添加DIBAL-H(1.0M甲苯溶液;43mL),且將反應混合物在0℃下攪拌1h。將含3N HCl之水(50mL)添加至混合物中直至其變成白色漿料,且接著再添加1N HCl(20mL)。收集有機層,且水層用EtOAc(3×100mL)萃取。合併之有機層經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;配於石油醚之5% EtOAc)進行純化,得到呈白色固體狀之標題化合物(7g,88%):mp 115-116℃;1H NMR(400MHz,CDCl3)δ 10.41(s,1H),9.35(m,1H),8.22(m,1H),7.90(d,J=8.0Hz,1H),7.75(m,3H),4.95(s,2H);ESIMS m/z 248.88([M+H]+)。
向經攪拌之4-(溴甲基)-1-萘甲醛(7g,28mmol)於DMF(100mL)中之溶液中添加鄰苯二甲醯亞胺鉀(7.3g,39.5mmol),且將混合物在85℃下加熱2h。將反應混合物冷卻至環境溫度且用水(100mL)稀釋。所獲得之固體藉由過濾來分離且在真空下乾燥,得到呈白色固體狀之標題化合物(8.8g,98%):mp 190-192℃;1H NMR(400MHz,
CDCl3)δ 10.39(s,1H),9.25(m,1H),8.41(m,1H),8.10(d,J=8.0Hz,1H),7.95(m,4H),7.80(m,4H),7.61(m,4H),5.39(s,2H);ESIMS m/z 316.09([M+H]+);IR(薄膜)1708cm-1。
在環境溫度下向經攪拌之4-((1,3-二側氧基異吲哚啉-2-基)甲基)-1-萘甲醛(9g,28.5mmol)於1,4-二噁烷(100mL)中之溶液中添加K2CO3(6g,42.8mmol)及溴化甲基三苯基鏻(15.3g,35.7mmol)。將反應混合物在100℃下加熱14h且接著冷卻至環境溫度。過濾反應混合物,且在減壓下濃縮所獲得之濾液。藉由急驟層析(SiO2,100-200篩目;配於石油醚之20% EtOAc)進行純化,得到呈白色固體狀之標題化合物(6g,67%):mp 146-147℃;1H NMR(400MHz,CDCl3)δ 8.35(m,2H),7.95(m,4H),7.65(m,4H),7.39(m,1H),5.81(m,1H),5.45(m,1H),5.21(s,2H);ESIMS m/z 314.13([M+H]+)。
向經攪拌之2-((4-乙烯基萘-1-基)甲基)異吲哚啉-1,3-二酮(1.5g,4.79mmol)於1,2-二氯苯(15mL)中之溶液中添加1-(1-溴-2,2,2-三氟乙基)-3,4,5-三氯苯(3.2g,9.5mmol)、CuCl(24mg,0.24mmol)及2,2-聯吡啶(0.149g,0.95mmol),且所得反應混合物用氬氣脫氣30min且接著在180℃下攪拌14h。在利用TLC認為反應完全之後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。藉由急驟層析(SiO2,100-200篩目;配於石油醚之25-30% EtOAc)進行純化,得到呈灰白色固體狀之標題化合物(1.5g,56%):mp 158-160℃;1H NMR(400MHz,CDCl3)δ 8.40(m,1H),7.89(m,2H),7.74(m,2H),7.64(m,2H),7.58(m,2H),7.46(s,2H),7.36(m,2H),6.31(m,1H),5.30(s,2H),4.21(m,1H);ESIMS m/z 572.08([M-H]-)。
向經攪拌之(E)-2-((4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)萘-1-基)甲基)異吲哚啉-1,3-二酮(0.4g,0.7mmol)於EtOH中之溶液中添加水合肼(0.18g,3.5
mmol),且將所得反應混合物在80℃下加熱2h。過濾反應混合物,且濃縮濾液。將殘餘物溶解於CH2Cl2中,且溶液用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。標題化合物以膠狀液體狀分離(150mg,50%)。此反應中所獲得之產物未經進一步純化即用於下一步驟。
向經攪拌之(4-溴苯基)肼鹽酸鹽(0.5g,2.2mmol)於AcOH(8mL)中之溶液中添加鄰苯二甲酸酐(0.398g,2.690mmol),且將反應混合物在130℃下在氮氣氛圍下攪拌1h。反應混合物用NaHCO3飽和水溶液淬滅且過濾,得到固體。藉由管柱層析(SiO2,配於石油醚之0-10% EtOAc)進行純化,得到呈固體狀之標題化合物(60mg,84%):mp 205-206℃;1H NMR(400MHz,CDCl3)δ 8.71(s,1H),7.99(m,4H),7.32(d,J=8.8Hz,2H),6.79(d,J=8.8Hz,2H);ESIMS m/z 314.95([M-H]-)。
向2-(4-溴苯基胺基)異吲哚啉-1,3-二酮(2g,6.mmol)於1,2-二甲氧基乙烷(20mL)及水(4mL)中之溶液中依序添加乙烯基酸酐吡啶複合物(4.57g,18.98mmol)及K2CO3(1.3g,9.5mmol)以及Pd(PPh3)4(0.219g,0.189mmol)。將所得反應混合物在150℃下在微波中加熱30min,且接著在減壓下濃縮。藉由管柱層析(SiO2,配於石油醚之15% EtOAc)進行純化,得到呈固體狀之標題化合物(200mg,13%):mp 174-176℃;1H NMR(400MHz,CDCl3)δ 8.65(s,1H),7.94(m,4H),7.29(d,J=8.4Hz,2H),6.72(d,J=8.4Hz,2H),6.61(m,1H),5.61(d,J=17.6Hz,1H),5.05(d,J=11.2Hz,1H);ESIMS m/z 263.18([M-H]-)。
向經攪拌之2-(4-乙烯基苯基胺基)異吲哚啉-1,3-二酮(0.3g,1.1mmol)於1,2-二氯苯(5mL)中之溶液中添加CuCl(0.022g,0.273mmol)、2,2-聯吡啶(0.07g,0.46mmol)及5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(0.77g,2.27
mmol)。反應混合物用氬氣脫氣30min且在180℃下加熱2h。接著在減壓下濃縮反應混合物,且殘餘物藉由管柱層析(SiO2,配於石油醚之0-30% EtOAc)純化,得到呈固體狀之標題化合物(450mg,75%):mp 187-189℃;1H NMR(400MHz,CDCl3)δ 8.75(s,1H),7.96(m,4H),7.82(s,2H),7.37(d,J=8.8Hz,1H),6.73(d,J=8.4Hz,2H),6.61(m,2H),6.58(m,1H),4.59(m,1H);ESIMS m/z 523.05([M-H]-)。
向經攪拌之(E)-2-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯基胺基)異吲哚啉-1,3-二酮(0.16g,0.31mmol)於EtOH(5mL)中之溶液中添加水合肼(0.076g,1.52mmol),且將反應混合物在85℃下加熱1h。將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液,得到呈固體狀之標題化合物(0.08g,66%),該標題化合物未經進一步純化即用於下一步驟。
向經攪拌之4-乙烯基苯基酸(2g,13mmol)、2-羥基異吲哚啉-1,3-二酮(3.63g,24.53mmol)及CuCl(1.214g,12.26mmol)於1,2-二氯乙烷(50mL)中之溶液中添加吡啶(1.065g,13.48mmol),且將所得反應混合物在環境溫度下攪拌48h。反應混合物用水稀釋且用CHCl3萃取。合併之CHCl3層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2;配於石油醚之20% EtOAc)進行純化,得到呈白色固體狀之標題化合物(2g,63%):mp 129-131℃;1H NMR(400MHz,CDCl3)δ 7.93(d,J=2.0Hz,2H),7.82(d,J=3.2Hz,2H),7.38(d,J=2.0Hz,2H),7.14(d,J=2.0Hz,2H),6.70(m,1H),5.83(d,J=16.0Hz,1H),5.22(d,J=10.8Hz,1H);ESIMS m/z 266.12([M+H]+)。
向經攪拌之2-(4-乙烯基苯氧基)異吲哚啉-1,3-二酮(0.3g,1.1mmol)於1,2-二氯苯(10mL)中之溶液中添加1-(1-溴乙基)-3,4,5-三氯苯(769mg,2.26mmol)、CuCl(22
mg,0.22mmol)及2,2-聯吡啶(35mg,0.44mmol),且將所得反應混合物用氬氣脫氣30min且加熱至180℃後持續24h。將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。粗物質藉由管柱層析(SiO2,100-200篩目;配於石油醚之20% EtOAc)純化,得到呈固體狀之標題化合物(0.29g,50%):1H NMR(400MHz,CDCl3)δ 7.90(m,1H),7.62(m,2H),7.50(m,1H),7.40(s,2H),7.12(s,1H),6.90(m,2H),6.60(m,2H),6.20(m,1H),4.08(m,1H);ESIMS m/z 524.09([M-H]-)。
向經攪拌之(E)-2-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯氧基)異吲哚啉-1,3-二酮(0.2g,0.4mmol)於EtOH中之溶液中添加水合肼(0.1g,1.9mmol),且將所得反應混合物在90℃下加熱1h。過濾反應混合物,且濃縮濾液。將殘餘物溶解於CH2Cl2中,用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈膠狀液體狀之粗標題化合物(0.08g,53%):1H NMR(400MHz,CDCl3)δ 7.40(s,2H),6.98(s,1H),6.82(s,2H),6.48(m,1H),6.20(m,1H),5.02(s,1H),4.08(m,1H);ESIMS m/z 394.94([M-H]-)。
向經攪拌之(E)-(2-氯-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.3g,0.8mmol)於CH2Cl2(10mL)中之溶液中添加乙酸酐(0.12mL,1.14mmol),及TEA(0.217mL,1.52mmol),且將所得反應混合物在環境溫度下攪拌6h。反應混合物用水稀釋且用CH2Cl2萃取。合併之CH2Cl2層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;配於己烷之30-50% EtOAc)進行純化,得到呈灰白色固體狀之標題化合物(0.2g,60%)mp 107-109℃;1H NMR(400MHz,CDCl3)δ 7.37(m,3H),7.28(m,4H),6.60(d,J=16.0Hz,1H),6.36(dd,J=16.0,8.0Hz,1H),5.75(br s,1H),4.46(d,J=6Hz,2H),4.01(m,1H),2.11(s,3H);ESIMS m/z 402.00([M+H]+)。
表1中之化合物CC2-CC6根據實例72中揭示之程序製造。另外,表1中之化合物DC56根據實例72中揭示之程序自化合物DC55製造。
向經攪拌之(E)-(2-氯-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.3g,0.8mmol)於DMF(5mL)中之溶液中添加2,2,2-三氟-丙酸(97mg,0.76mmol)、HOBt.H2O(174mg,1.14mmol)及EDC.HCl(217mg,1.14mmol)及DIPEA(196mg,1.52mmol),且將所得反應混合物在環境溫度下攪拌18h。反應混合物用水稀釋且用EtOAc萃取。合併之EtOAc層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;配於己烷之30-50%EtOAc)進行純化,得到呈灰白色固體狀之標題化合物(0.2g,60%):mp 127-128℃;1H NMR(400MHz,CDCl3)δ 7.42(m,4H),7.24(m,2H),6.53(d,J=16.0Hz,1H),6.36(dd,J=16.0,8.0Hz,1H),5.86(br s,1H),4.51(d,J=6.0Hz,2H),4.05(m,1H),2.02(s,3H);ESIMS m/z 436.03([M+H]+)。
表1中之化合物CC8-CC28根據實例73中揭示之程序製造。
步驟1:(E)-1-(吡啶-2-基)-N-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)苯甲基)甲胺.將(E)-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)苯基)甲胺(0.46g,1mmol)溶解於MeOH(3mL)中。向此溶液中添加吡啶-2-甲醛(0.107g,1mmol)。將反應混合物攪拌1h。1h後,添加NaBH4(0.076g,2mmol)且在環境溫度下靜置3h。濃縮反應混合物,得到油狀殘餘物。藉由急驟管柱層析(SiO2,100-200篩目;配於己烷之30-50% EtOAc)進行純化,得到呈淺黃色液體狀之標題化合物(0.22g,40%):1H NMR(400MHz,CDCl3)δ 8.58(d,J=4.8Hz,1H),7.74(m,1H),7.62(m,2H),7.52(m,1H),7.4(s,2H),7.3(m,1H),7.2(m,2H),6.60(d,J=16.0Hz,1H),6.38(dd,J=16.0,8.0Hz,1H),4.10(m,1H),4.02(s,2H),3.96(s,2H);ESIMS m/z 552.95([M+H]+);IR(薄膜)3338,1114,808cm-1。
步驟2:(E)-N-(吡啶-2-基甲基)-N-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)苯甲基)環丙烷甲醯胺. 將(E)-1-(吡啶-2-基)-N-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲基)甲胺(0.27g,0.05mmol)吸收於CH2Cl2(3mL)中。向此溶液中添加TEA(0.14mL,0.1mmol)。將反應混合物攪拌10min。10min
後,將反應混合物冷卻至0℃,且添加環丙基羰基氯(0.08mL,0.075mmol)。將反應混合物在環境溫度下攪拌1h,且接著用水及氰基硼氫化鈉飽和水溶液洗滌。有機層經無水Na2SO4乾燥且蒸發,獲得淺黃色膠狀物質(0.15g,50%):1H NMR(400MHz,CDCl3)δ 8.58(d,J=4.6Hz,1H),7.74(m,1H),7.62(m,2H),7.52(m,1H),7.4(s,2H),7.3(m,1H),7.2(m,2H),6.60(d,J=16.0Hz,1H),6.38(dd,J=16.0,8.0Hz,1H),5.02(s,1H),4.8(s,1H),4.8(d,J=10Hz,2H),4.10(m,1H),1.8(m,1H),1.2(m,2H),0.6(m,2H);ESIMS m/z 620.86([M-H]-);IR(薄膜)1645,1115,808cm-1。
(E)-N-(2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)-3-(甲基硫基)丙醯胺(0.15g,0.28mmol)在環境溫度下用含過硫酸氫鉀(0.175g,0.569mmol)之1:1丙酮:水(20mL)處理4h。蒸發丙酮,獲得白色固體(0.095g,60%):mp 101-104℃;1H NMR(400MHz,CDCl3)δ 7.41(m,4H),7.24(m,1H),6.53(d,J=16.0Hz,1H),6.35(dd,J=16.0,8.0Hz,1H),6.12(br s,1H),4.53(m,2H),4.10(m,1H),3.42(m,2H),2.91(s,3H),2.78(m,2H);ESIMS m/z 559.75([M-H]-)。
在0℃下向經攪拌之(E)-(2-氯-4-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.2g,0.5mmol)於CH2Cl2(5mL)中之溶液中添加TEA(0.141mL,1mmol)及異氰酸乙酯(0.053g,0.75mmol),且將反應混合物在0℃下攪拌1h。反應混合物用CH2Cl2稀釋。有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於己烷之30-50% EtOAc)進行純化,得到呈固體狀之標題化合物(0.141g,60%):mp 177-178℃;1H NMR(400MHz,CDCl3)δ 7.58(m,2H),7.41(m,3H),7.24(m,1H),6.53(d,J=16.0Hz,1H),6.35(dd,J=16.0,8.0Hz,1H),4.70(br s,1H),4.43(s,2H),4.08(m,1H),3.21(m,2H),1.25(m,3H);ESIMS m/z 463([M-H]-)。
表1中之化合物CC32-CC35根據實例76中揭示之程序製造。
在0℃下向經攪拌之(E)-(2-氯-4-(3-(3,4,5-三氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.2g,0.5mmol)於CH2Cl2(5mL)中之溶液中添加TEA(0.141mL,1mmol)及N,N-二甲基胺甲醯氯(0.08g,0.075mmol),且將反應混合物在0℃下攪拌1h。反應混合物用CH2Cl2稀釋。有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於己烷之30-50% EtOAc)進行純化,得到呈固體狀之標題化合物(0.15g,60%):1H NMR(400MHz,CDCl3)δ 7.39(m,4H),7.28(m,1H),6.54(d,J=16.0Hz,1H),6.34(dd,J=16.0,8.0Hz,1H),4.97(br s,1H),4.38(d,J=6.0Hz,2H),4.10(m,1H),2.9(s,3H),2.7(s,3H);ESIMS m/z 497([M-H]-);IR(薄膜)3350,1705,1114,808cm-1。
在0℃下向經攪拌之(E)-(2-氯-4-(3-(3,4,5-三氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.2g,0.5mmol)於CH2Cl2(5mL)中之溶液中添加TEA(0.141mL,1mmol)及異硫氰酸乙酯(0.053g,0.75mmol),且將反應混合物在0℃下攪拌1h。反應混合物用CH2Cl2稀釋。有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,
100-200篩目;配於己烷之30-50% EtOAc)進行純化,得到呈固體狀之標題化合物(0.14g,60%):mp 88-91℃;1H NMR(400MHz,CDCl3)δ 7.49(d,J=8Hz,1H),7.41(d,J=7.2Hz,2H),7.26(m,2H),6.50(d,J=16Hz,1H),6.35(dd,J=16.0,8.0Hz,1H),6.0(br s,1H),5.73(br s,1H),4.80(br s,2H),4.09(m,1H),1.23(m,3H);ESIMS m/z 515.01([M+H]+)。
表1中之化合物CC38根據實例78中揭示之程序製造。
在0℃下向經攪拌之(E)-(2-氯-4-(3-(3,4,5-三氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.2g,0.5mmol)於CH2Cl2(5mL)中之溶液中添加TEA(0.141mL,1mmol)及二碳酸二第三丁酯(0.163mL,0.75mmol),且將反應混合物在環境溫度下攪拌4h。反應混合物用CH2Cl2稀釋。有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於己烷之10-20% EtOAc)進行純化,得到呈白色固體狀之標題化合物(0.147g,60%):1H NMR(400MHz,CDCl3)δ 7.39(m,4H),7.28(m,1H),6.54(d,J=16.0Hz,1H),6.34(dd,J=16.0,8.0Hz,1H),
4.97(br s,1H),4.38(d,J=6.0Hz,2H),4.10(m,1H),1.53(s,9H);ESIMS m/z 526.09([M-H]-);IR(薄膜)3350,1705,1114,808cm-1。
表1中之化合物CC40根據實例79中揭示之程序製造。
在0℃下向經攪拌之(E)-(2-氯-4-(3-(3,4,5-三氯苯基)-4,4,4-三氟丁-1-烯-1-基)苯基)甲胺(0.2g,0.5mmol)於CH2Cl2(5mL)中之溶液中添加TEA(0.141mL,1mmol)及2-氯-2-側氧基乙酸甲酯(0.09g,0.75mmol),且將反應混合物在0℃下攪拌1h。反應混合物用CH2Cl2稀釋。有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於己烷之20% EtOAc)進行純化,得到呈固體狀之標題化合物(0.12g,50%):1H NMR(400MHz,CDCl3)δ 7.48(m,1H)。7.43(m,3H),7.38(m,1H),7.23(s,1H),6.55(d,J=16.0Hz,1H),6.36(dd,J=16.0,8.0Hz,1H),4.60(d,J=4.4Hz,2H),4.18(m,1H),3.85(s,3H);ESIMS m/z 512.22([M-H]-);IR(薄膜)1740,1701,1114,808cm-1。
向經攪拌之2,2,2-三氟乙胺鹽酸鹽(0.1g,0.77mmol)於CH2Cl2(10mL)中之溶液中逐滴添加三甲基鋁(2M甲苯溶液;0.39mL,0.77mmol),且將反應混合物在25℃下攪拌30min。在25℃下將(E)-2-((2-氯-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)-2-側氧基乙酸甲酯(0.2g,0.38mmol)於CH2Cl2(5mL)中之溶液逐滴添加至反應混合物中。將反應混合物在回流下攪拌18h,冷卻至25℃,用0.5N HCl溶液(50mL)淬滅且用EtOAc(2×50mL)萃取。合併之有機萃取物用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目;配於正己烷之20%-40% EtOAc)純化,得到標題化合物(0.13g,60%):mp 161-163℃;1H NMR(400MHz,DMSO-d 6)δ 9.45(br s,2H),7.90(s,2H),7.75(s,1H),7.46(s,1H),7.28(s,1H),6.93(m,1H),6.75(m,1H),4.80(m,1H),4.40(s,2H),3.90(s,2H);ESIMS m/z 578.96([M-H]-)。
向經攪拌之N-(2-氯-4-乙烯基苯甲基)吡啶-2-胺(0.3g,1.22mmol)於1,2-二氯苯(5mL)中之溶液中添加5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(0.83g,2.44mmol)、CuCl(24mg,0.24mmol)及2,2-聯吡啶(76mg,0.48mmol)。所得反應混合物用氬氣脫氣30min且接著將其在180℃下攪拌24h。在利用TLC認為反應完全之後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。藉由急驟層析(SiO2,100-200篩目;配於正己烷之15% EtOAc)進行純化,得到呈灰白色固體狀之標題化合物(0.2g,35%):mp 140-142℃;1H NMR(400MHz,CDCl3)δ 8.11(d,J=4.0Hz,1H),7.40(m,5H),7.22(m,1H),6.61(m,2H),6.35(m,2H),4.94(br s,1H),4.61(d,J=6.4Hz,2H),4.11(m,1H);ESIMS m/z 505.39([M+H]+)。
向經攪拌之(E)-(3-氯-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)吡啶-2-基)甲胺(0.1g,0.2mmol)於
CH2Cl2(5mL)中之溶液中添加3,3,3-三氟丙酸(45mg,0.350mmol)、EDC.HCl(67mg,0.350mmol)、HOBt.H2O(71mg,0.467mmol)及DIPEA(60.2mg,0.467mmol),且將反應混合物在環境溫度下攪拌18h。反應混合物用CH2Cl2稀釋且用水洗滌。合併之CH2Cl2層用鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;配於石油醚之15% EtOAc)進行純化,得到呈淺黃色液體狀之標題化合物(30mg,35%):1H NMR(400MHz,CDCl3)δ 8.41(s,1H),7.77(s,1H),7.47(br s,1H),7.40(s,2H),6.58(d,J=16.0Hz,1H),6.45(dd,J=16.0,8.0Hz,1H),4.68(d,J=4.0Hz,2H),4.14(m,1H),3.24(q,J=10.8Hz,2H);ESIMS m/z 536.88([M-H]-);IR(薄膜)3320,1674,1114,808。
表1中之化合物CC45根據實例83中揭示之程序製造。
向經攪拌之(E)-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)萘-1-基)甲胺(0.1g,0.22mmol)於CH2Cl2(8mL)中之溶液中添加3,3,3-三氟丙酸(0.032g,0.24mmol)、HOBt.H2O(52mg,0.33mmol)、EDC.HCl(0.065g,0.33mmol)
及DIPEA(0.044g,0.45mmol),且將所得反應混合物在環境溫度下攪拌18h。反應混合物用水稀釋且用EtOAc(3×30mL)萃取。合併之EtOAc層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2,100-200篩目;配於正己烷之15% EtOAc)進行純化,得到呈膠狀物質之標題化合物(60mg,50%):mp 151-153℃;1H NMR(400MHz,CDCl3)δ 8.06(m,1H),7.61(m,4H),7.48(s,2H),7.44(d,J=8.0Hz,1H),7.38(m,1H),6.42(m,1H),5.92(br s,1H),4.92(m,2H),4.24(m,1H),3.12(m,2H);ESIMS m/z 554.04([M-H]-)。
表1中之化合物CC47-CC48根據實例84中揭示之程序製造。
在0℃下向經攪拌之(E)-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)萘-1-基)甲胺(0.1g,0.22mmol)於CH2Cl2中之溶液中添加TEA(0.064mL,0.44mmol)及異氰酸乙酯(0.023mL,0.33mmol),且將反應混合物在0℃下攪拌1h。反應混合物用CH2Cl2稀釋。有機層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於己烷之30% EtOAc)進行純化,得到呈固
體狀之標題化合物(0.07g,60%):mp 84-87℃;1H NMR(400MHz,CDCl3)δ 8.06(m,1H),7.98(m,1H),7.61(m,3H),7.48(s,2H),7.44(d,J=8.0Hz,1H),7.38(m,2H),6.42(m,1H),4.92(s,2H),4.6(br s,1H),4.24(m,1H),3.21(m,2H),1.2(t,J=4.6Hz,3H);ESIMS m/z 515.33([M+H]+)。
向經攪拌之(E)-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)肼(0.1g,0.3mmol)於CH2Cl2(10mL)中之溶液中添加DIPEA(65mg,0.51mmol)、HOBt.H2O(59mg,0.38mmol)、EDC.HCl(73mg,0.38mmol)及環丙烷甲醯氯(0.024g,0.28mmol),且將反應混合物在環境溫度下攪拌1h。反應混合物用NaHCO3飽和水溶液稀釋且用CH2Cl2萃取。合併之CH2Cl2層用鹽水洗滌,經無水Na2SO4乾燥,且在減壓下濃縮。藉由急驟管柱層析(SiO2;配於石油醚之5-25% EtOAc)進行純化,得到呈固體狀之標題化合物(65mg,55%):mp 138-140℃;1H NMR(400MHz,CDCl3)δ 9.81(s,1H),7.90(s,1H),7.84(s,2H),7.34(d,J=8.4Hz,2H),6.65(d,J=15.6Hz,1H),6.61(m,1H),6.57(s,1H),6.48(dd,J=15.6,8.8Hz,1H),4.74(m,1H),1.64(m,1H),0.75(m,4H);ESIMS m/z 461.32([M-H]-)。
表1中之化合物CC51根據實例86中揭示之程序製造。
向經攪拌之(E)-O-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)羥胺(0.15g,0.38mmol)於CH2Cl2(5mL)中之溶液中添加EDC.HCl(0.109g,0.569mmol)、HOBt.H2O(0.087g,0.569mmol)、DIPEA(0.097g,0.758mmol)及環丙烷甲酸(0.049g,0.569mmol)。將所得反應混合物在環境溫度下攪拌18h。反應混合物用水稀釋且用CHCl3(35mL)萃取。合併之CHCl3層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由急驟管柱層析(SiO2;配於己烷之20% EtOAc)進行純化,得到呈棕色液體狀之標題化合物(0.06g,34%):1H NMR(400MHz,CDCl3)δ 7.40(s,2H),7.18(s,1H),7.08(s,1H),6.85(m,1H),6.45(m,1H),6.65(m,1H),6.20(m,1H),5.55(s,1H),4.08(m,1H),1.90(m,1H),1.30-1.10(m,4H);ESIMS m/z 464.87([M-H]-)。
表1中之化合物CC53根據實例87中揭示之程序製造。
將(E)-3,3,3-三氟-N-(4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲基)丙醯胺(133mg,0.269mmol)及二甲亞碸(DMSO;10mL)饋入硼酸矽小瓶中。將混合物置放於0.6至1公尺(m)之一排八個115瓦特(watt)Sylvania FR48T12/350BL/VHO/180螢光燈管黑光及四個115瓦特Sylvania(日光)F48T12/D/VHO直式T12螢光燈管光中持續72h。將混合物在真空中濃縮且藉由逆相層析純化,得到呈無色油狀物之標題化合物(11mg,8%):1H NMR(300MHz,CDCl3)δ 7.28(s,2H),7.25(m,2H),7.10(d,J=8.0Hz,2H),6.89(d,J=11.4Hz,1H),6.07(br s,1H),6.01(m,1H),4.51(d,J=5.8Hz,2H),4.34(m,1H),3.12(q,J=7.5Hz,2H);13C NMR(101MHz,CDCl3)δ 162.44,137.20,135.38,135.23,134.82,134.68,131.71,129.00,128.80,128.69,128.10,127.96,122.63,76.70,47.33(q,J=28Hz),43.59,42.12(q,J=30Hz);ESIMS m/z 504([M+H]+)。
表1中之化合物DC46、AC93、AC94根據實例88中揭示之程序製造。
標題化合物在兩個步驟中經由以下合成:1-(3-氯苯基)-2,2,2-三氟乙醇(DI1,如實例1中方法B之步驟1中製備);以無色黏性油狀物分離(1.5g,75%):1H NMR(400MHz,CDCl3)δ 7.50(s,1H),7.42-7.35(m,3H),5.02(m,1H),2.65(br s,1H))及實例1中步驟2且經分離(0.14g,22%):1H NMR(400MHz,CDCl3)δ 7.50(br s,1H),7,42-7.35(m,3H),5.07(m,1H)。
以下化合物根據實例89中揭示之程序製造。
(1-溴-2,2,2-三氟乙基)苯(DI4)
分離2,2,2-三氟-1-苯基乙醇(DI3)(10g,80%):1H NMR(300MHz,CDCl3)δ 7.48(m,2H),7.40(m,3H),5.02(m,1H),2.65(d,J=7.1Hz,1H)。標題化合物(DI4)以液體狀分離(8.0g,60%):1H NMR(400MHz,CDCl3)δ 7.50(m,2H),7.40(m,3H),5.00(q,J=7.5Hz,1H)。
1-(1-溴-2,2,2-三氟乙基)-3,5-二甲基苯(DI20)
1-(3,5-二甲基苯基)-2,2,2-三氟乙醇(DI19)以灰白色固體狀分離:1H NMR(400MHz,CDCl3)δ 7.05(s,2H),7.02(s,1H),4.95(m,1H),2.32(s,6H);ESIMS m/z 204
([M]-)。標題化合物(DI20)經分離(3.0g,51%)。
1-(1-溴-2,2,2-三氟乙基)-2,4-二氯苯(DI22)
1-(2,4-二氯苯基)-2,2,2-三氟乙醇(DI21)以灰白色粉末狀分離(5.3g,61%):mp 49-51℃;1H NMR(400MHz,CDCl3)δ 7.62-7.66(d,1H),7.42-7.44(d,1H),7.32-7.36(d,1H),5.6(m,1H),2.7(s,1H);ESIMS m/z 244([M]+)。標題化合物(DI22)經分離(3.2g,50%):1H NMR(400MHz,CDCl3)δ 7.62-7.72(m,1H),7.4-7.42(m,1H),7.3-7.38(m,1H),5.7-5.8(m,1H)。
1-(1-溴-2,2,2-三氟乙基)-2,3-二氯苯(DI24)
1-(2,3-二氯苯基)-2,2,2-三氟乙醇(DI23)以淺黃色油狀物分離(5.2g,60%):1H NMR(400MHz,CDCl3)δ 7.62-7.64(d,1H),7.52-7.54(m,1H),7.29-7.33(t,1H),5.6-5.76(m,1H),2.7(s,1H);ESIMS m/z 243.9([M]+)。標題化合物(DI24)以油狀物分離(8.7g,60%):1H NMR(400MHz,CDCl3)δ 7.62-7.71(m,1H),7.44-7.52(m,1H),7.27-7.3(s,1H),5.81-5.91(m,1H)。
2-(1-溴-2,2,2-三氟乙基)-1,4-二氯苯(DI26)
1-(2,5-二氯苯基)-2,2,2-三氟乙醇(DI25)以黃色油狀物分離(4.1g,60%):1H NMR(400MHz,CDCl3)δ 7.68-7.7(s,1H),7.3-7.37(m,2H),5.51-5.6(m,1H),2.7(s,1H);ESIMS m/z 244([M]+))。標題化合物(DI26)經分離(3.0g,60%):1H NMR(400MHz,CDCl3)δ 7.7-7.78(m,1H),7.3-7.4(m,2H),5.7-5.8(m,1H)。
1-(1-溴-2,2,2-三氟乙基)-3,5-雙(三氟甲基)苯(DI28)
1-(3,5-雙(三氟甲基)苯基)-2,2,2-三氟乙醇(DI27)經分離(3.8g,60%):1H NMR(400MHz,CDCl3)δ 7.98(m,3H),5.25(m,1H),3.2(br,1H);ESIMS m/z 312.2([M]+)。製備標題化合物(DI28)且以粗物質繼續使用。
1-(1-溴-2,2,2-三氟乙基)-2,3,5-三氯苯(DI30)
2,2,2-三氟-1-(2,3,5-三氯苯基)乙醇(DI29)以白色固體狀分離(4.0g,60%):mp 113-115℃;1H NMR(400MHz,CDCl3)δ 7.62(d,1H),7.50(d,1H),5.60-5.70(m,1H),2.75
(s,1H);ESIMS m/z 278.0([M+])。標題化合物(DI30)經分離(2.9g,60%):1H NMR(400MHz,CDCl3)δ 7.70(d,1H),7.50(d,1H),5.72-5.82(m,1H)。
1-(1-溴-2,2,2-三氟乙基)-3-氯-5-(三氟甲基)苯(DI32)
1-(3-氯-5-(三氟甲基)苯基)-2,2,2-三氟乙醇(DI31)以淺黃色油狀物分離(2.0g,50%):1H NMR(400MHz,CDCl3)δ 7.51(m,3H),5.08(m,1H),2.81(s,1H);ESIMS m/z 278.1([M]+)。標題化合物(DI32)以油狀物分離(2.0g,40%):ESIMS m/z 342([M]+)。
5-(1-溴-2,2,2-三氟乙基)-1,3-二氯-2-甲氧基苯(DI34)
1-(3,5-二氯-4-甲氧基苯基)-2,2,2-三氟乙醇(DI33)以灰白色固體狀分離(0.8g,60%);mp 92-95℃:1H NMR(400MHz,CDCl3)δ 7.41(s,2H),5.00(m,1H),3.89(s,3H),2.64(m,1H);ESIMS m/z 274([M]+)。標題化合物(DI34)以無色液體狀分離(0.6g,57%)。
標題化合物在兩個步驟中經由以下合成:1-(3,5-二氟苯基)-2,2,2-三氟乙醇(DI35,如實例1中方法A之步驟1中製備;以無色油狀物分離(0.2g,75%):1H NMR(400MHz,CDCl3)δ 7.05(m,2H),6.88(m,1H),5.06(m,1H),2.66(s,1H);ESIMS m/z 212([M]+)及實例1中步驟2且經分離(3.2g,50%);1H NMR(400MHz,CDCl3)δ 7.05(m,2H),6.86(m,1H),5.03(q,J=7.4Hz,1H)。
以下化合物根據實例90中揭示之程序製造。
1-(1-溴-2,2,2-三氟乙基)-4-氯苯(DI38)
1-(4-氯苯基)-2,2,2-三氟乙醇(DI37)以無色油狀物分離(5.0g,99%):1H NMR(400MHz,CDCl3)δ 7.44-7.38(m,4H),5.05(m,1H),2.55(s,1H);ESIMS m/z 210([M]+)。標題化合物(DI38)經分離(3.0g,46%):1H NMR(400MHz,CDCl3)δ 7.45(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),5.10(q,J=7.2Hz,1H)。
1-(1-溴-2,2,2-三氟乙基)-4-甲氧基苯(DI40)
2,2,2-三氟-1-(4-甲氧基苯基)乙醇(DI39)以淺黃色液體狀分離:1H NMR(400MHz,CDCl3)δ 7.41(d,J=8.8Hz,2H),6.95(m,J=8.8Hz,2H),5.00(m,1H),3.82(s,3H),2.44(s,1H);ESIMS m/z 206.1([M]+)。標題化合物(DI40)經分離(3.8g,62%)。
1-(1-溴-2,2,2-三氟乙基)-4-氟苯(DI42)
2,2,2-三氟-1-(4-氟苯基)乙醇(DI41)以無色油狀物分離(5g,99%):1H NMR(400MHz,CDCl3)δ 7.48-7.45(m,2H),7.13-7.07(m,2H),5.06(m,1H),2.53(s,1H);ESIMS m/z 194([M]+)。製備標題化合物(DI42)且以粗中間物形式繼續使用。
1-(1-溴-2,2,2-三氟乙基)-4-甲基苯(DI44)
2,2,2-三氟-1-(對甲苯基)乙醇(DI43)以無色油狀物分離(5.0g,99%):1H NMR(400MHz,CDCl3)δ 7.37(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),5.02(m,1H),2.46(m,
1H),2.37(s,3H);ESIMS m/z 190([M]+)。標題化合物(DI44)經分離(3.0g,45%)。
1-(1-溴-2,2,2-三氟乙基)-3-氟苯(DI46)
2,2,2-三氟-1-(3-氟苯基)乙醇(DI45)以無色黏性油狀物分離(2.8g,93%):1H NMR(400MHz,CDCl3)δ 7.41(m,1H),7.25(m,2H),7.14(m,1H),5.06(m,1H),2.60(s,1H);ESIMS m/z 194([M]+)。標題化合物(DI46)經分離(2.0g,61%)。
1-(1-溴-2,2,2-三氟乙基)-2-氟苯(DI48)
2,2,2-三氟-1-(2-氟苯基)乙醇(DI47)以無色油狀物分離(2.5g,99%):1H NMR(400MHz,CDCl3)δ 7.40(m,1H),7.43(m,1H),7.24(m,1H),7.13(m,1H),5.42(m,1H),2.65(s,1H);ESIMS m/z 194([M]+)。標題化合物(DI48)經分離(2.0g,61%):1H NMR(400MHz,CDCl3)δ 7.61(m,1H),7.40(m,1H),7.23(m,1H),7.10(m,1H),5.40(m,1H);GCMS m/z 255([M-H]-)。
向經攪拌之4-氟苯甲醛(10.0g,80.6mmol)於DMF(150mL)中之溶液中添加K2CO3(13.3g,96.7mmol)及1,2,4-三唑(6.67g,96.7mmol),且將所得反應混合物在120℃下攪拌6h。反應完全(根據TLC)後,反應混合物用水稀釋且用EtOAc(3×100mL)萃取。合併之EtOAc層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈固體狀之標題化合物(9.0g,65%):mp 145-149℃:1H NMR(400MHz,CDCl3)δ 10.08(s,1H),8.70(s,1H),8.16(s,1H),8.06(d,J=8.0Hz,2H),7.92(d,J=8.0Hz,2H);ESIMS m/z 173.9([M+H]+)。
以下化合物根據實例91中揭示之程序製造。
5-甲醯基-2-(1H-1,2,4-三唑-1-基)苯甲腈(DI49)
標題化合物經分離(2.8g,60%);1H NMR(400MHz,CDCl3)δ 10.10(s,1H),8.98(s,1H),8.35(s,1H),8.30(d,1H),8.22(s,1H),8.07(d,1H);IR(薄膜)3433,3120,1702,1599,1510cm-1。
2-氯-4-(1H-1,2,4-三唑-1-基)苯甲醛(DI50)
標題化合物以灰白色固體狀分離(3.0g,40%):mp 149-151℃;1H NMR(400MHz,CDCl3)δ 10.05(s,1H),8.74(s,1H),8.17(s,1H),8.10(s,1H),7.90(m,2H);ESIMS m/z 208.10([M+H]+)。
5-甲基-4-(1H-1,2,4-三唑-1-基)苯甲醛(DI51)
標題化合物以白色固體狀分離(0.5g,74%):mp 109-111℃;1H NMR(400MHz,D6-DMSO)δ 10.06(s,1H),9.00(s,1H),8.30(s,1H),7.99(s,1H),7.92(d,J=9.2Hz,1H),7.69(d,J=9.2Hz,1H),2.30(s,3H);ESIMS m/z 188.13([M+H]+)。
向經攪拌之2-氟-5-甲醯基苯甲腈(0.5g,3.3mmol)於DMF(25mL)中之溶液中添加K2CO3(0.68g,4.95
mmol)及3-硝基-1,2,4三唑(0.45g,4.2mmol),且將所得反應混合物在環境溫度下攪拌14h。反應完全(TLC)後,反應混合物用水稀釋且用EtOAc萃取。合併之EtOAc層用水及鹽水洗滌,接著經Na2SO4乾燥且在減壓下濃縮,得到呈淺黃色固體狀之標題化合物(0.36g,45%):mp 170-172℃;1H NMR(300MHz,DMSO-d 6)δ 10.12(s,1H),9.61(s,1H),8.69(s,1H),8.45(d,J=9.3Hz,1H),8.23(d,J=9.3Hz,1H);ESIMS m/z 242.3([M-H]-);IR(薄膜)2238,1705,1551,1314cm-1。
向經攪拌之4-氟苯甲醛(5.0g,40.32mmol)於DMF(50mL)中之溶液中添加K2CO3(3.34g,40.32mmol)及3-甲基-1,2,4-三唑(3.34g,40.32mmol),且將所得反應混合物在環境溫度下攪拌4h。反應完全(TLC)後,反應混合物用水稀釋且用EtOAc萃取(3×)。合併之EtOAc層用水及鹽水洗滌,接著經Na2SO4乾燥且在減壓下濃縮,得到呈白色固體狀之標題化合物(4.1g,60%):mp 125-128℃;1H NMR(400MHz,CDCl3)δ 10.05(s,1H),8.76(s,1H),8.02(d,2H),7.85(d,2H),2.50(s,3H);ESIMS m/z 188.04([M+H]+)。
以下化合物根據實例93中揭示之程序製造。
4-(1H-1,2,4-三唑-1-基)-3-(三氟甲基)苯甲醛(DI54)
標題化合物以白色固體狀分離(1.05g,60%):mp 81-83℃;1H NMR(400MHz,CDCl3)δ 10.15(s,1H),8.43(s,1H),8.37(s,1H),8.25(d,J=7.2Hz,1H),8.18(s,1H),7.79(d,J=7.2Hz,1H);ESIMS m/z 241.0([M]+)。
4-(3-硝基-1H-1,2,4-三唑-1-基)苯甲醛(DI55)
標題化合物以淺黃色固體狀分離(0.10g,23%):mp 159-161℃;1H NMR(400MHz,CDCl3)δ 10.10(s,1H),8.89(s,1H),8.15(m,2H),8.00(m,2H);ESIMS m/z 217.11([M-H]-)。
3-溴-4-(1H-1,2,4-三唑-1-基)苯甲醛(DI56)
標題化合物以白色固體狀分離(3.2g,51%):mp 126-128℃;1H NMR(400MHz,CDCl3)δ 10.04(s,1H),8.69(s,1H),8.27(M,1H,8.18(s,1H)7.99(d,J=9.2Hz,1H),
7.76(d,J=9.2Hz,1H);ESIMS m/z 250.9([M]+)。
5-甲醯基-2-(3-甲基-1H-1,2,4-三唑-1-基)苯甲腈(DI57)
標題化合物以白色固體狀分離(0.13g,30%):mp 147-149℃;1H NMR(400MHz,CDCl3)δ 10.07(s,1H),8.89(s,1H),8.32(d,J=1.8Hz,1H),8.24(dd,J=8.6,1.3Hz,1H),8.06(d,J=8.6Hz,1H),2.54(s,3H);ESIMS m/z 213.09([M+H]+);IR(薄膜)2239,1697cm-1。
3-硝基-4-(1H-1,2,4-三唑-1-基)苯甲醛(DI58)
標題化合物以淺黃色固體狀分離(3.0g,60%):mp 116-118℃;1H NMR(400MHz,CDCl3)δ 10.15(s,1H),8.48(s,1H),8.46(s,1H),8.26(d,J=6.9Hz,1H),8.16(s,1H),7.83(d,J=6.9Hz,1H);ESIMS m/z 219.00([M+H]+)。
在室溫下向經攪拌之4-[1,2,4]三唑-1-基-苯甲醛(9.0g,52mmol)於1,4-二噁烷(100mL)中之溶液中添加K2CO3(10.76g,78mmol)及溴化甲基三苯基鏻(22.2g,62.4
mmol)。將所得反應混合物加熱至70℃後持續18h。反應完全(TLC)後,將反應混合物冷卻至室溫且過濾,且在減壓下濃縮所獲得之濾液。藉由急驟層析(SiO2,100-200篩目;配於石油醚之25-30% EtOAc)進行純化,得到呈白色固體狀之標題化合物(5.6g,63%):ESIMS m/z 172.09([M+H]+)。
以下化合物根據實例94中揭示之程序製造。
1-(2-甲基-4-乙烯基苯基)-1H-1,2,4-三唑(DI60)
標題化合物以灰白色固體狀分離(1.5g,76%):1H NMR(400MHz,CDCl3)δ 8.25(s,1H),8.11(s,1H),7.35(m,2H),7.27(d,J=8.7Hz,1H),6.74(m,1H),5.82(d,J=17.3Hz,1H),5.36(d,J=10.0Hz,1H),2.25(s,3H);ESIMS m/z 186.14([M+H]+)。
2-(1H-1,2,4-三唑-1-基)-5-乙烯基苯甲腈(DI61)
標題化合物以灰白色固體狀分離(1.40g,71%):mp 126-129℃;1H NMR(400MHz,CDCl3)δ 8.76(s,1H),8.18(s,1H),7.82-7.84(m,1H),7.72-7.80(m,2H),6.70-6.80(dd,J=17.6,10.8Hz,1H),5.90-5.95(d,J=17.6Hz,1H),5.50-5.70(d,J=10.8Hz,1H);ESIMS m/z 197.03([M+H]+)。
向經攪拌之5-甲醯基-2-(3-硝基-1H-1,2,4-三唑-1-基)苯甲腈(0.36g,1.49mmol)於1,4-二噁烷(25mL)中之溶液中添加K2CO3(0.3g,2.2mmol)及溴化甲基三苯基鏻(0.63g,1.79mmol)。將所得反應混合物加熱至100℃後持續18h。反應完全(TLC)後,將反應混合物冷卻至室溫且過濾,且在減壓下濃縮所獲得之濾液。藉由急驟層析(SiO2,100-200篩目;配於石油醚之25-30% EtOAc)進行純化,得到呈固體狀之標題化合物(0.25g,70%):mp 103-105℃;1H NMR(400MHz,DMSO-d 6)δ 9.50(s,1H),8.34(m,1H),7.98(d,J=7.8Hz,1H),7.68(d,J=7.8Hz,1H),6.87(m,1H),6.20(d,J=15.7Hz,1H),5.56(d,J=11.8Hz,1H);ESIMS m/z 240.27([M-H]-);IR(薄膜)2240,1514,1312cm-1。
以下化合物根據實例95中揭示之程序製造。
1-(3-氯-4-乙烯基苯基)-1H-1,2,4-三唑(DI63)
標題化合物以灰白色固體狀分離(2.3g,80%):mp 134-137℃;1H NMR(400MHz,CDCl3)δ 8.56(s,1H),8.11(s,1H),7.76(s,1H),7.70(d,J=9.0Hz,1H),7.57(d,J=9.0Hz,1H),7.10(m,1H),5.80(d,J=17.2Hz,1H),5.47
(d,J=12.4Hz,1H);ESIMS m/z 206.04([M+H]+。
3-甲基-1-(4-乙烯基苯基)-1H-1,2,4-三唑(DI64)
標題化合物以白色固體狀分離(0.6g,60%):mp 109-111℃;1H NMR(400MHz,CDCl3)δ 8.42(s,1H),7.40-7.60(m,4H),6.70-7.00(dd,J=17.6,10.8Hz,1H),5.80(d,J=17.6Hz,1H),5.30(d,J=17.6Hz,1H),2.50(s,3H);ESIMS m/z 186.20([M+H]+)。
1-(2-(三氟甲基)-4-乙烯基苯基)-1H-1,2,4-三唑(DI65)
標題化合物以無色油狀物分離(0.6g,60%):1H NMR(400MHz,CDCl3)δ 8.32(s,1H),8.14(s,1H),7.84(s,1H),7.72(d,J=8.0Hz,1H),7.50(d,J=7.6Hz,1H),6.70-6.90(dd,J=17.6,10.8Hz,1H),5.90-6.00(d,J=17.6Hz,1H),5.50-5.80(d,J=10.8Hz 1H);ESIMS m/z 240.16([M+H]+)。
3-硝基-1-(4-乙烯基苯基)-1H-1,2,4-三唑(DI66)
標題化合物以淺黃色固體狀分離(61mg,20%):
mp 137-139℃;1H NMR(400MHz,CDCl3)δ 8.60(s,1H),7.68(d,J=7.7Hz,2H),7.60(d,J=8.3Hz,2H),6.77(dd,J=17.7,10.8,1H),5.87(d,J=17.7Hz,1H),5.42(d,J=10.8Hz,1H);ESIMS m/z 217.28([M+H]+)。
1-(2-溴-4-乙烯基苯基)-1H-1,2,4-三唑(DI67)
標題化合物以白色固體狀分離(1.2g,40%):mp 75-77℃;1H NMR(400MHz,CDCl3)δ 8.48(s,1H),8.12(s,1H),7.75(s,1H)7.42(s,2H),6.70(m,1H),5.83(d,J=18Hz,1H),5.42(d,J=12Hz,1H);ESIMS m/z 249.1([M]+)。
2-(3-甲基-1H-1,2,4-三唑-1-基)-5-乙烯基苯甲腈(DI68)
標題化合物以灰白色固體狀分離(0.6g,60%):mp 96-97℃;1H NMR(400MHz,CDCl3)δ 8.66(s,1H),7.80(s,1H),7.74(m,2H),6.73(dd,J=17.6Hz,10.8Hz,1H),5.88(d,J=17.6Hz,1H),5.49(d,J=10.8Hz,1H),2.52(s,3H);ESIMS m/z 211.10([M+H]+);IR(薄膜)2229cm-1。
1-(2-硝基-4-乙烯基苯基)-1H-1,2,4-三唑(DI69)
標題化合物以黃色固體狀分離(1.78g,60%):
mp 102-104℃;1H NMR(400MHz,CDCl3)δ 8.40(s,1H),8.12(s,1H),8.02(s,1H),7.72-7.76(d,J=8.0Hz,1H),7.52-7.56(d,J=17.6Hz,1H),6.70-6.82(dd,J=17.6,10.8Hz,1H),5.85-6.00(d,J=17.6Hz,1H),5.50-5.60(d,J=10.8,Hz 1H);ESIMS m/z 217.0([M+H]+)。
步驟1. 5-溴-2-氟-3-甲基苯甲醛:在-78℃下經10min之時間向經攪拌之二異丙胺(4.01g,39.88mmol)於THF(20mL)中之溶液中緩慢地逐滴添加n-BuLi(1.6M於己烷中)(19.9mL,31.91mmol),將反應混合物在-78℃下攪拌30min。在-78℃下添加4-溴-1-氟-2-甲基苯(5.0g,26.6mmol)於THF(30.0mL)中之溶液,且將反應混合物在相同溫度下攪拌1h。添加DMF(5.0mL),且在-78℃下再攪拌30min。反應利用TLC監測;接著反應混合物在0℃下用1N HCl溶液(水溶液)淬滅。水層用Et2O萃取,用水及飽和鹽水溶液洗滌。合併之有機層經無水Na2SO4乾燥且在減壓下濃縮,獲得粗化合物,該粗化合物藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之5% EtOAc溶離)純化,得到呈白色固體狀之標題化合物(3.6g,64%);mp 48-50℃:1H NMR(400MHz,CDCl3)δ 8.33(s,1H),8.22(s,1H),7.67(s,1H),7.60(s,1H),6.75(dd,J=17.6,10.8Hz,1H),5.92(dd,J=17.6,
10.8Hz,1H),5.52(d,J=17.6Hz,1H),2.21(s,3H);ESIMS m/z 211.35([M-H]-)。
步驟2. (E)-5-溴-2-氟-3-甲基苯甲醛肟:在環境溫度下向經攪拌之5-溴-2-氟-3-甲基苯甲醛(3.5g,16.2mmol)於乙醇(50.0mL)中之溶液中添加NaOAc(2.0g,24.3mmol)及羥胺鹽酸鹽(1.69g,24.3mmol)。將反應混合物在環境溫度下攪拌3h。在旋轉蒸發儀上濃縮反應混合物,獲得粗化合物,該粗化合物用水洗滌,過濾且在真空下乾燥,得到呈白色固體狀之標題化合物:mp 126-127℃;1H NMR(400MHz,CDCl3)δ 8.32(s,1H),7.73(d,J=2.4Hz,1H),7.51(s,1H),7.34(d,J=2.4Hz,1H),2.25(s,3H);ESIMS m/z 232.10([M+H]+)。
步驟3. 5-溴-2-氟-3-甲基苯甲腈:將經攪拌之(E)-5-溴-2-氟-3-甲基苯甲醛肟(0.5g,2.2mmol)於乙酸酐(5.0mL)中之溶液加熱至回流後持續18h。反應混合物用水稀釋且用EtOAc萃取。合併之EtOAc層用鹽水洗滌且經Na2SO4乾燥且在減壓下濃縮,得到呈淡棕色膠狀物質之粗化合物(0.4g,粗物質):ESIMS m/z 213.82([M+H]+)。
步驟4. 5-溴-3-甲基-2-(1H-1,2,4-三唑-1-基)苯甲腈(DI71):在環境溫度下向經攪拌之5-溴-2-氟-3-甲基苯甲腈(1.0g,47.716mmol)於DMF(10.0mL)中之溶液中依序添加K2CO3(1.95g,14.14mmol)及1H-1,2,4-三唑(0.811g,9.433mmol)。將反應混合物加熱至140℃後持續18h。將反應混合物冷卻至環境溫度,用水稀釋且用EtOAc(2×100mL)
萃取。合併之EtOAc層用鹽水洗滌且經Na2SO4乾燥且在減壓下濃縮,得到粗化合物,該粗化合物藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之30% EtOAc溶離)純化,得到呈粉紅色固體狀之標題化合物(0.6g,49%):1H NMR(400MHz,CDCl3)δ 8.39(s,1H),8.23(s,1H),7.91(d,J=2.4Hz,2H),2.21(s,3H),ESIMS m/z 262.57([M+H]+);IR(薄膜)2231,554cm-1。
步驟5. 3-甲基-2-(1H-1,2,4-三唑-1-基)-5-乙烯基苯甲腈(DI70):5-溴-3-甲基-2-(1H-1,2,4-三唑-1-基)苯甲腈(0.6g,2.3mmol)、K2CO3(0.95g,6.87mmol)、乙烯基酸酐(0.82g,3.43mmol)及三苯基膦(0.13g,0.114mmol)於甲苯(20.0mL)中之混合物經攪拌且用氬氣脫氣30min。將反應混合物加熱至回流後持續18h。將反應混合物冷卻至環境溫度,用水稀釋且用EtOAc(2×100mL)萃取。合併之EtOAc層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到粗化合物,該粗化合物藉由急驟管柱層析(SiO2,100-200篩目;用配於石油醚之30% EtOAc溶離)純化,得到呈粉紅色固體狀之標題化合物(0.25g,52%):1H NMR(400MHz,CDCl3)δ 8.33(s,1H),8.22(s,1H),7.67(s,1H),7.60(s,1H),6.75(dd,J=17.6,10.8Hz,1H),5.92(d,J=17.6,1H),5.52(d,J=10.8Hz,1H),2.21(s,3H),ESIMS m/z 211.35([M+H]+);IR(薄膜)2236,1511cm-1。
以下化合物根據實例96之步驟4及5中揭示之程序製造。
1-(2-氟-4-乙烯基苯基)-1H-1,2,4-三唑(DI72)
1-(4-溴-2-氟苯基)-1H-1,2,4-三唑(DI73)以淺黃色固體狀分離(3.0g,75%):mp 113-116℃;1H NMR(400MHz,CDCl3)δ 8.69(s,1H),8.13(m,2H),7.50(m,1H),7.21(m,1H);ESIMS m/z 241.93([M]+)。標題化合物(DI72)以黃色固體狀分離(1.0g,71%):mp 67-70℃;1H NMR(400MHz,CDCl3)δ 8.67(s,1H),8.13(s,1H),7.94(m,1H),7.41(m,1H),7.24(s,1H),6.75(dd,J=17.6,10.8Hz,1H),5.81(d,J=17.6Hz,1H),5.37(d,J=10.8Hz,1H);ESIMS m/z 190.00([M+H]+)。
在-78℃下向經攪拌之1-(4-乙烯基-苯基)-1H-[1,2,4]三唑(1g,5.8mmol)於25mL THF中之溶液中添加n-BuLi(0.37g,5.8mmol)且攪拌30min。向此溶液中添加含N-甲氧基-N-甲基乙醯胺之THF(0.66g,6.4mmol),且將所得反應混合物在環境溫度下攪拌16h。反應混合物用NH4Cl飽和水溶液淬滅且用EtOAc(3×50mL)萃取。合併之EtOAc層用鹽水洗滌且經硫酸鈉乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目,配於石油醚之40%
EtOAc)純化,得到呈灰白色固體狀之標題化合物(280mg,23%):mp 97-98℃;1H NMR(400MHz,CDCl3)δ 8.10(s,1H),7.50(d,2H),7.38(d,2H),6.68(dd,1H),5.85(d,1H),5.38(d,1H),2.75(s,3H);ESIMS m/z 214.14([M+H]+)。
在-78℃下向經攪拌之1-(4-乙烯基-苯基)-1H-[1,2,4]三唑(1g,5.8mmol)於25mL THF中之溶液中添加n-BuLi(0.37g,5.8mmol)且攪拌30min。向此溶液中添加含N-甲氧基N-甲基環丙氧化物之THF(0.82g,6.4mmol),且將所得反應混合物在環境溫度下攪拌16h。反應混合物用NH4Cl飽和水溶液淬滅且用EtOAc(3×25mL)萃取。合併之EtOAc層用鹽水洗滌且經硫酸鈉乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目,配於石油醚之40% EtOAc)純化,得到呈灰白色固體狀之標題化合物(420mg,30%):mp 90-91℃;1H NMR(400MHz,CDCl3)δ 8.12(s,1H),7.50(d,J=7.8Hz,2H),7.38(d,J=7.8Hz,2H),6.75(dd,J=16.3,10.7Hz,1H),5.81(d,J=16.3Hz,1H),5.35(d,J=10.7Hz,1H),3.22(m,1H),1.27(m,2H),1.18(m,2H);ESIMS m/z 240.18([M+H]+);IR(薄膜)2922,1630cm-1。
在-78℃下向經攪拌之1-(4-乙烯基-苯基)-1H-[1,2,4]三唑(1g,5.8mmol)於50mL THF中之溶液中添加n-BuLi(0.41g,6.4mmol)且攪拌30min。向此溶液中添加含二硫化二甲基之THF(0.6g,6.43mmol),且將所得反應混合物在環境溫度下攪拌16h。反應混合物用NH4Cl飽和水溶液淬滅且用EtOAc(3×25mL)萃取。合併之EtOAc層用鹽水洗滌且經硫酸鈉乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目,配於石油醚之40% EtOAc)純化,得到呈灰白色固體狀之標題化合物(0.6g,48%):mp 68-70℃;1H NMR(400MHz,CDCl3)δ 7.96(s,1H),7.05(m,4H),6.75(dd,J=16.4,10.7Hz,1H),5.81(d,J=16.4Hz,1H),5.35(d,J=10.7Hz,1H),2.73(s,3H);ESIMS m/z 218.09([M+H]+)。
在-78℃下向經攪拌之1-(4-乙烯基-苯基)-1H-[1,2,4]三唑(0.5g,2.9mmol)於10mL THF中之溶液中添加n-BuLi(0.22g,3.5mmol)且攪拌30min。向此溶液
中添加含碘代甲烷之THF(0.50g,3.5mmol),且將所得反應混合物在環境溫度下攪拌16h。反應混合物用NH4Cl飽和水溶液淬滅且用EtOAc(3×25mL)萃取。合併之EtOAc層用鹽水洗滌且經硫酸鈉乾燥且在減壓下濃縮。粗化合物藉由急驟層析(SiO2,100-200篩目,配於石油醚之40% EtOAc)純化,得到呈淺棕色液體狀之標題化合物(250mg,46%):1H NMR(400MHz,CDCl3)δ 7.93(s,1H),7.55(d,J=9Hz,2H),7.42(d,J=9Hz,2H),6.76(dd,J=18,11Hz,1H),5.83(d,J=18Hz,1H),5.38(d,J=11Hz,1H),2.55(s,3H);ESIMS m/z 186.13([M+H]+);IR(薄膜)1517,1386,1182,847cm-1。
向經攪拌之1-(1-溴-2,2,2-三氟-乙基)-3,5-二氯-苯(2.0g,6.51mmol)於1,2-二氯苯(25mL)中之溶液中添加1-(4-乙烯基-苯基)-1H-[1,2,4]三唑(2.22g,13.0mmol)、CuCl(64mg,0.65mmol)及2,2-聯吡啶(0.2g,1.3mmol)。所得反應混合物用氬氣脫氣30min,接著將其在180℃下攪拌24h。反應完全(TLC)後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。藉由急驟層析(SiO2,100-200篩目;配於石油醚之25-30% EtOAc)進行純化,得到呈灰白
色固體狀之標題化合物(0.8g,32%):mp 93-97℃;1H NMR(300MHz,CDCl3)δ 8.56(s,1H),8.11(s,1H),7.68(d,J=8.4Hz,2H),7.54(d,J=8.4Hz,2H),7.38(t,J=1.8Hz,1H),7.29(s,2H),6.62(d,J=15.6Hz,1H),6.42(dd,J=15.6,8.2Hz,1H),4.15(m,1H);ESIMS m/z 398.05([M+H]+)。
表1中之化合物DC2-DC37、DC44、DC45、DC47-49、DC50、DC51、DC54、DC58、DC60、DC62及DC63-DC67根據實例97中揭示之程序製造。
向經攪拌之2-(3-硝基-1H-1,2,4-三唑-1-基)-5-乙烯基苯甲腈(0.9g,3.7mmol)於1,2-二氯苯(10mL)中之溶液中添加5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(2.5g,7.5mmol)、CuCl(73mg,0.74mmol)及2,2-聯吡啶(0.23g,1.49mmol),且所得反應混合物用氬氣脫氣30min,且接著將其在180℃下攪拌14h。反應完全(TLC)後,將反應混合物冷卻至環境溫度且過濾,且在減壓下濃縮濾液。藉由急驟層析(SiO2,100-200篩目,配於石油醚之25-30% EtOAc)進行純化,得到呈灰白色固體狀之標題化合物(0.9g,50%):mp 70-73℃;1H NMR(300MHz,CDCl3)δ 8.86(s,1H),7.88(m,3H),7.44(s,2H),6.67(d,J=16.0Hz,1H),6.56(dd,J=
16.0,7.6Hz,1H),4.19(m,1H);ESIMS m/z 436.11([M-2H]-)。
向經攪拌之(E)-2-(3-硝基-1H-1,2,4-三唑-1-基)-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲腈(0.6g,1.2mmol)於MeOH(10mL)中之溶液中添加鋅粉(0.39g,5.98mmol)及NH4Cl飽和水溶液(5mL),且將所得反應混合物在環境溫度下攪拌2h。反應完全(TLC)後,在減壓下濃縮反應物質。反應物質用CH2Cl2稀釋,經由Celite®床過濾,且在減壓下濃縮所獲得之濾液,得到呈固體狀之標題化合物(0.5g,89%):mp 72-75℃;1H NMR(300MHz,DMSO-d 6)δ 8.72(s,1H),8.26(s,1H),8.01(d,J=8.4Hz,1H),7.91(s,2H),7.77(d,J=8.4Hz,1H),6.42(dd,J=15.6,9.2Hz,1H),6.83(d,J=15.6Hz,1H),5.87(s,2H),4.89(m,1H);ESIMS m/z 469.95([M-H]-)。
表1中之化合物DC38根據實例99中揭示之程序製造。此外,除使用甲酸銨代替NH4Cl外,表1中之化合物DC55根據實例99中揭示之程序自化合物DC54製造。
在環境溫度下向經攪拌之(E)-2-(3-胺基-1H-1,2,4-三唑-1-基)-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲腈(0.1g,0.21mmol)於CH2Cl2中之溶液中添加環丙基羰基氯(0.045g,0.42mmol),且將反應混合物在環境溫度下攪拌2h。反應混合物用CH2Cl2稀釋且用水及鹽水洗滌且經Na2SO4乾燥。在減壓下濃縮,且藉由製備型HPLC純化,得到呈固體狀之標題化合物(0.09g,79%):mp 104-107℃;1H NMR(300MHz,CDCl3)δ 8.78(s,2H),7.83(s,1H),7.80(m,2H),7.42(s,2H),6.65(d,J=16.4Hz,1H),6.51(dd,J=7.6,8.0Hz,1H),4.17(m,1H),2.16(m,2H),1.25(m,4H),1.00(m,4H);ESIMS m/z 609.98([M+H]+);IR(薄膜)2234,1714,1114,807cm-1。
在0℃下向經攪拌之(E)-2-(3-胺基-1H-1,2,4-三唑-1-基)-5-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲腈
(0.15g,0.31mmol)於CH2Cl2中之溶液中添加TEA(0.1g,1mmol)及環丙基羰基氯(0.04g,0.38mmol),且將反應混合物在0℃下攪拌1h。反應混合物用CH2Cl2稀釋且用水及鹽水洗滌且經Na2SO4乾燥。在減壓下濃縮,且藉由管柱層析(SiO2,100-200篩目)進行純化,得到呈固體狀之標題化合物(66mg,34%):mp 109-112℃;1H NMR(300MHz,DMSO-d 6)δ 10.94(br s,1H),8.36(s,1H),8.08(m,J=8.4Hz,1H),7.91(s,2H),7.84(d,J=8.4Hz,1H),7.13(dd,J=15.6,9.2Hz,1H),6.87(d,J=15.6Hz,1H),4.92(m,1H),1.99(br s,1H),0.82(s,4H);ESIMS m/z 540.04([M+H]+);IR(薄膜)3233,2233,1699,1114,807cm-1。
表1中之化合物DC39根據實例101中揭示之程序製造。
向經攪拌之4-溴苯乙酮(10g,50mmol)於DMF(100mL)中之溶液中添加1,2,4-三唑(5g,75mmol)、Cs2CO3(32.6g,100.5mmol)及CuI(1.4g,10.1mmol),且將所得反應混合物回流48h。反應完全(根據TLC)後,將反應混合物冷卻至環境溫度且用水(200mL)稀釋且用EtOAc萃取。合併之有機層用鹽水洗滌且經Na2SO4乾燥且在減壓
下濃縮。藉由用Et2O洗滌來純化,得到呈固體狀之標題化合物(5g,96%):1H NMR(400MHz,CDCl3)δ 8.71(s,1H),8.16,(s,1H),8.13(d,J=8.6Hz,2H),7.83(d,J=8.6Hz,2H),2.66(s,3H);ESIMS m/z 186.02([M-H]-)。
步驟1. 1-(4-(1-(三甲基矽氧基)乙烯基)苯基)-1H-1,2,4-三唑(DI76)在0℃下向經攪拌之1-(4-(1H-1,2,4-三唑-1-基)苯基)乙酮(4.5g,24.0mmol)於CH2Cl2中之溶液中添加TEA(3.7g,36.1mmol)及三氟甲磺酸三甲基矽烷酯(8g,36mmol),且將所得反應混合物攪拌1h。反應混合物用NaHCO3飽和水溶液及醚之混合物淬滅。醚層經分離,用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到標題化合物(5.5g),將該標題化合物直接用於下一步驟。
步驟2. 1-(4-(1H-1,2,4-三唑-1-基)苯基)-3-(3,5-二氯苯基)-4,4,4-三氟丁-1-酮(DI75):一經攪拌之1-(4-(1-(三甲基矽氧基)乙烯基)苯基)-1H-1,2,4-三唑(6g,23mmol)及1-(1-溴-2,2,2-三氟-乙基)-3,5-二氯苯(7.1g,34.7mmol)於1,2-二氯苯(30mL)中之溶液用氬氣脫氣。添加CuCl(0.23g,2.31mmol)及2,2-聯吡啶(0.73g,4.63mmol)至上述反應混合物中,且將所得反應混合物加熱至180℃後持續18h。
反應完全(根據TLC)後,將反應混合物吸收於矽膠上且藉由管柱層析(SiO2;配於石油醚之10% EtOAc)純化,得到呈固體狀之標題化合物(3g,31%):1H NMR(400MHz,CDCl3)δ 8.67(s,1H),8.15(s,1H),8.10(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.33(m,1H),7.30(m,2H),4.20(m,1H),3.63(m,2H);ESIMS m/z 412.14([M-H]-)。
向冷卻至0℃之1-(4-(1H-1,2,4-三唑-1-基)苯基)-3-(3,5-二氯苯基)-4,4,4-三氟丁-1-酮(300mg,0.726mmol)於THF中之溶液中逐滴添加溴化甲基鎂(450mg,5mmol)。將反應物在0℃下攪拌3h,接著反應混合物用NH4Cl飽和水溶液淬滅且用EtOAc萃取。合併之EtOAc層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於石油醚之20%-25% EtOAc)進行純化,得到呈固體狀之標題化合物(100mg,32%):1H NMR(400MHz,CDCl3)δ兩種非對映異構體8.58(s,1H,次峰),8.48(s,1H,主峰),8.13(s,1H,次峰),8.09(s,1H,主峰),7.70(d,J=9.0Hz,2H,次峰),7.53(d,J=9.0Hz,2H,次峰),7.40(d,J=9.0Hz,2H,主峰),7.31(m,1H,次峰),7.27(d,J=9.0Hz,2H,主峰),7.20(m,2H,次峰),7.01(m,1H,
主峰),6.75(m,2H,主峰),350(m,1H),2.50(m,2H),1.56(s,3H,主峰),1.54(s,3H,次峰);ESIMS m/z 430.05([M+H]+)。
向2-(4-(1H-1,2,4-三唑-1-基)苯基)-4-(3,5-二氯苯基)-5,5,5-三氟戊-2-醇(100mg,0.233mmol)於甲苯中之溶液中添加催化量之對甲苯磺酸,且經12h之時段藉由共沸蒸餾來移除水。將反應混合物冷卻至室溫且溶解於EtOAc中。溶液用NaHCO3飽和水溶液及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。藉由管柱層析(SiO2,100-200篩目;配於石油醚之20%-25% EtOAc)進行純化,得到呈固體狀之標題化合物(30mg,31%)。
在-78℃下向經攪拌之(E)-5-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(1H-1,2,4-三唑-1-基)苯甲腈(0.3g,0.71mmol)於甲苯(10mL)中之溶液中逐滴添加氫化
二異丁基鋁(DIBAL-H,1.0M甲苯溶液;0.85mL),且將反應混合物在-78℃下攪拌20min。反應混合物在添加1N HCl溶液情況下淬滅,接著水層用EtOAc萃取(2×)。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟管柱層析(SiO2;配於石油醚之50% EtOAc)純化,得到呈黃色油狀物之標題化合物。
表1中之化合物DC53根據實例123中揭示之程序製造。
向經攪拌之(E)-5-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(1H-1,2,4-三唑-1-基)苯胺(0.3g,0.7mmol)於CH2Cl2(10mL)中之溶液中添加TEA(0.155mL,1.09mmol)及碘代甲烷(0.124g,0.873mmol)。將反應物在環境溫度下攪拌18h。CH2Cl2層用水及鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟管柱層析(SiO2;配於石油醚之50% EtOAc)純化,得到呈黃色半固體狀之標題化合物(0.07g,70%)。
將(E)-5-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(1H-1,2,4-三唑-1-基)苯甲酸乙酯(0.2g,0.4mmol)於6N HCl(10mL)中之溶液在100℃下攪拌18h。將反應物冷卻至環境溫度,產生白色固體沈澱。過濾沈澱,得到呈白色固體狀之標題化合物(0.12g,60%)。
將(E)-5-(3-(3,5-二氯苯基)-4,4,4-三氟丁-1-烯-1-基)-2-(1H-1,2,4-三唑-1-基)苯甲腈(0.3g,0.71mmol)、NaOAc(0.087g,1.065mmol)及氯化羥銨(0.072g,1.065mmol)於9:1乙醇/水混合物(10mL)中之溶液在70℃下攪拌8h。將反應物冷卻至環境溫度,且蒸發乙醇。將殘餘物溶解於水中且用EtOAc萃取(2×)。合併之有機層用鹽水洗滌,經Na2SO4乾燥且在減壓下濃縮,得到呈灰白色固體狀之標題化合物。
步驟1. (E)-3-(4-(1H-1,2,4-三唑-1-基)苯基)-1-(3,5-二氯苯基)丙-2-烯-1-酮:向1-(3,5-二氯苯基)乙酮(0.5g,2.6mmol)於乙醇(20mL)中之溶液中添加4-(1H-1,2,4-三唑-1-基)苯甲醛(0.46g,2.65mmol),且將反應物冷卻至0℃。接著添加含NaOH(0.22g,5.29mmol)之水(10mL),且使反應物在0℃下攪拌2h。反應物用EtOAc萃取,且合併之有機層經Na2SO4乾燥且在減壓下濃縮,得到標題化合物(0.149g,17%);ESIMS m/z 430.05([M+H]+)344.08
步驟2. (E)-4-(4-(1H-1,2,4-三唑-1-基)苯基)-2-(3,5-二氯苯基)-1,1,1-三氟丁-3-烯-2-醇(DC69):在0℃下向(E)-3-(4-(1H-1,2,4-三唑-1-基)苯基)-1-(3,5-二氯苯基)丙-2-烯-1-酮(1g,3mmol)於THF(150mL)中之溶液中添加三氟甲基三甲基矽烷(0.517g,3.644mmol)及氟化四正丁基銨(TBAF)(1.0M,1mL)。使反應物緩慢溫至環境溫度且攪拌2h。接著將反應物冷卻至0℃,且添加5M HCl溶液,且將反應物在環境溫度下再攪拌4h。反應物用CH2Cl2萃取,且合併之有機層經Na2SO4乾燥且在減壓下濃縮。粗化合物藉由急驟管柱層析(SiO2;配於己烷之25% EtOAc)純化,得到呈灰白色固體狀之標題化合物(0.3g,25%)。
步驟3. (E)-1-(4-(3-(3,5-二氯苯基)-4,4,4-三氟-3-甲氧基丁-1-烯-1-基)苯基)-1H-1,2,4-三唑(DC70):在0℃下
向(E)-4-(4-(1H-1,2,4-三唑-1-基)苯基)-2-(3,5-二氯苯基)-1,1,1-三氟丁-3-烯-2-醇(0.15g,0.36mmol)於THF(5mL)中之溶液中添加NaH(60%,10mg,0.44mmol)。使反應物在0℃下攪拌30min,接著緩慢添加碘代甲烷(61mg,0.44mmol),且使反應物溫至環境溫度且攪拌4h。反應物用NH4Cl水溶液淬滅且用CH2Cl2萃取。合併之有機層經Na2SO4乾燥且在減壓下濃縮,得到呈灰白色固體狀之標題化合物(55mg,35%)。
向經攪拌之2-((第三丁氧基羰基)胺基)-2-甲基丙酸(4.58g,22.6mmol)於二氯甲烷(50mL)中之溶液中依序添加EDC.HCl(4.75g,24.8mmol)以及2,2,2-三氟乙胺(2.67g,27.0mmol)及DMAP(3.03g,24.8mmol)。將反應混合物在環境溫度下攪拌18h,接著用5% NaHSO4水溶液(2×)、10% HCl水溶液(1×)及NaHCO3飽和水溶液(2×)洗滌。有機相經乾燥(MgSO4)且在真空中濃縮,得到呈白色固體狀之標題化合物(2.97g,46%)。
以下分子根據實例128中揭示之程序製造:
(S)-(1-側氧基-1-((2,2,2-三氟乙基)胺基)丁-2-基)胺基甲酸第三丁酯
標題分子以白色固體狀分離:mp 108-111℃;1H NMR(400MHz,CDCl3)δ 6.90(s,1H),5.04(m,1H),4.07(m,1H),3.92(m,3H),1.87(m,1H),1.66(m,1H),1.44(s,9H),0.96(t,J=7.4Hz,3H);19F NMR(376MHz,CDCl3)δ -72.54;13C NMR(101MHz,CDCl3)δ 173.05,156.04,124.03(q,J=278.5Hz),80.30,55.56,40.43(q,J=34.7Hz),28.19,25.63,9.80;[α]D=-33.3(c,10.1mg/mL於CH2Cl2中)。
(1-側氧基-1-((2,2,2-三氟乙基)胺基)丁-2-基)胺基甲酸第三丁酯
標題分子以白色固體狀分離:mp 113-116℃;1H NMR(400MHz,CDCl3)δ 7.36(d,J=8.4Hz,1H),5.43-5.25(m,1H),4.16(m,1H),3.98(m,1H),3.82(m,1H),1.84(dt,J=14.0,7.0Hz,1H),1.66(dt,J=14.2,7.3Hz,1H),1.44(s,9H),0.95(t,J=7.3Hz,3H);19F NMR(376MHz,CDCl3)δ -72.51;13C NMR(101MHz,CDCl3)δ 172.94,156.02,124.47(q,J=380.8Hz),80.33,55.54,40.46(q,J=34.8Hz),28.19,25.61,9.79。
(2-側氧基-2-((1,1,1-三氟丙-2-基)胺基)乙基)胺基甲酸第三丁酯
標題分子以白色固體狀分離:mp 84-88℃;1H NMR(400MHz,CDCl3)δ 6.89(s,1H),5.44(t,J=5.8Hz,1H),4.77-4.48(m,1H),3.83(d,J=5.9Hz,2H),1.45(s,9H),1.33(d,J=7.0Hz,3H);19F NMR(376MHz,CDCl3)δ -77.63;13C NMR(101MHz,CDCl3)δ 169.84,156.33,125.19(q,J=280.9Hz),80.29,46.20(q,J=31.7Hz),44.15,28.11,13.88;EIMS m/z 270([M]+)。
(R)-(1-((2-氟乙基)胺基)-1-側氧基丙-2-基)胺基甲酸第三丁酯
標題分子以白色固體狀分離:mp 91-94℃;1H NMR(300MHz,DMSO-d 6)δ 7.98(bs,1H),6.87(t,J=7.2Hz,1H),4.47(t,J=4.8Hz,1H),4.32(t,J=5.1Hz,1H),3.97-3.92(m,1H),3.41-3.37(m,1H),3.33-3.28(m,1H),1.37(s,9H),1.16(d,J=7.3Hz,3H);ESIMS m/z 235.0([M+H]+)。
(3-側氧基-3-((2,2,2-三氟乙基)胺基)丙基)胺基甲酸第三丁酯
標題分子以白色固體狀分離:mp 123-125℃;1H
NMR(400MHz,CDCl3)δ 6.42-6.22(m,1H),5.07(s,1H),3.92(qd,J=9.1,6.4Hz,2H),3.43(q,J=6.2Hz,2H),2.50(t,J=6.0Hz,2H),1.43(s,9H);19F NMR(376MHz,CDCl3)δ -72.50;13C NMR(101MHz,CDCl3)δ 171.76,156.30,124.02(q,J=278.5Hz),79.67,40.53(q,J=34.8Hz),36.41,36.27,28.31。
(R)-(1-(乙基胺基)-1-側氧基丙-2-基)胺基甲酸第三丁酯
標題分子以白色固體狀分離:mp 88-93℃;1H NMR(400MHz,CDCl3)δ 6.35(s,1H),5.25-5.04(m,1H),4.21-3.99(m,1H),3.29(dd,J=7.5,5.9Hz,2H),1.45(s,8H),1.35(d,J=7.0Hz,3H),1.13(t,J=7.3Hz,3H);13C NMR(101MHz,CDCl3)δ 172.79,155.51,79.59,49.97,34.16,28.25,18.77,14.60。
(R)-(1-側氧基-1-((3,3,3-三氟丙基)胺基)丙-2-基)胺基甲酸第三丁酯
標題分子以灰白色固體狀分離:mp 101-105℃;1H NMR(300MHz,DMSO-d 6)δ 7.96(bs,1H),6.90(d,J=6.9Hz,1H),3.91-3.86(m,1H),3.34-3.19(m,2H),2.50-2.32(m,2H),1.37(s,9H),1.15(d,J=7.2Hz,3H)。
(R)-(1-側氧基-1-((2,2,2-三氟乙基)胺基)戊-2-基)胺基
甲酸第三丁酯
標題分子以白色固體狀分離:mp 107-122℃;1H NMR(400MHz,CDCl3))δ 6.90(s,1H),5.00(d,J=8.0Hz,1H),4.12(d,J=7.3Hz,1H),3.99-3.76(m,2H),1.87-1.73(m,1H),1.65-1.52(m,1H),1.44(s,9H),1.38(m,2H),0.94(t,J=7.3Hz,3H);19F NMR(376MHz,CDCl3)δ旋轉異構體-72.55,-73.27;13C NMR(101MHz,CD3OD)δ旋轉異構體176.08,157.86,次峰126.13(q,J=279.8Hz),主峰125.83(q,J=278.8Hz),80.65,55.90,次峰42.27(q,J=35.4Hz),主峰41.24(q,J=35.4Hz),35.50,28.73,20.04,14.03。
(R)-(3-甲基-1-側氧基-1-((2,2,2-三氟乙基)胺基)丁-2-基)胺基甲酸苯甲酯
標題分子以白色固體狀分離:mp 157-161℃;1H NMR(400MHz,CDCl3)δ 7.46-7.31(m,5H),6.57(d,J=8.3Hz,1H),5.34(d,J=8.9Hz,1H),5.11(s,2H),4.02(dq,J=16.1,8.8,7.7Hz,2H),3.78(td,J=9.0,4.7Hz,1H),2.15(q,J=6.7Hz,1H),0.97(d,J=6.8Hz,3H),0.94(d,J=6.8Hz,3H);19F NMR(376MHz,CDCl3)δ -72.44。
向含(2-甲基-1-側氧基-1-((2,2,2-三氟乙基)胺基)丙-2-基)胺基甲酸第三丁酯(2.61g,9.18mmol)之二氯甲烷(20mL)中添加含4M HCl之二噁烷(20mL)。將溶液在環境溫度下攪拌6h。在真空中濃縮反應混合物,得到呈白色固體狀之標題化合物(2.18g)。
以下分子根據實例129中揭示之程序製造:
氯化(R)-1-側氧基-1-((2,2,2-三氟乙基)胺基)丙-2-胺鎓
標題分子以白色固體狀分離:mp 210-213℃;1H NMR(400MHz,DMSO-d 6)δ 9.22(t,J=6.3Hz,1H),8.37-8.27(m,3H),4.07-3.95(m,2H),3.95-3.84(m,1H),1.38(d,J=7.0Hz,3H);19F NMR(376MHz,DMSO-d 6)δ -70.75;[α]D=-6.6(c,5.0mg/mL於MeOH中)。
氯化1-側氧基-1-((2,2,2-三氟乙基)胺基)丁-2-胺鎓
標題分子以白色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 9.12(t,J=5.7Hz,1H),8.19(s,3H),4.14-3.93(m,2H),3.78(t,J=6.0Hz,1H),1.81-1.71(m,2H),0.88(t,J
=7.2Hz,3H);ESIMS m/z 184.90([(M-TFA)+H]+);IR(薄膜)3269,1681,1158cm-1。
氯化2-側氧基-2-((1,1,1-三氟丙-2-基)胺基)乙胺鎓
標題分子以白色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 8.96(d,J=8.7Hz,1H),8.09(bs,3H),4.71-4.59(m,1H),3.64-3.62(m,2H),1.27(d,J=6.9Hz,3H);EIMS m/z 170.1([M]+)。
氯化(R)-1-((2-氟乙基)胺基)-1-側氧基丙-2-胺鎓
標題分子以白色固體狀分離:1H NMR(300MHz,DMSO-d 6)δ 8.76(t,J=5.1Hz,1H),8.21(bs,3H),4.54(t,J=5.1Hz,1H),4.38(t,J=4.8Hz,1H),3.85-3.79(m,1H),3.50-3.45(m,1H),3.41-3.36(m,1H),1.36(d,J=7.2Hz,3H);ESIMS m/z 135.1([M+H]+);IR(薄膜)3331,2983,,1660,1161,597cm-1。
氯化3-側氧基-3-((2,2,2-三氟乙基)胺基)丙-1-胺鎓
標題分子以白色固體狀分離:mp 193-197℃;1H NMR(400MHz,DMSO-d 6)δ 8.94(t,J=6.4Hz,1H),8.16(s,3H),3.99-3.79(m,2H),2.98(t,J=7.3Hz,2H),2.64(t,J=
7.3Hz,2H);19F NMR(376MHz,DMSO-d 6)δ -70.74。
氯化(R)-1-(乙基胺基)-1-側氧基丙-2-胺鎓
標題分子以白色固體狀分離:mp 223-236℃;1H NMR(400MHz,DMSO-d 6)δ 8.65(t,J=5.4Hz,1H),8.32(s,3H),3.89-3.66(m,1H),3.12(p,J=7.0Hz,2H),1.35(d,J=6.9Hz,3H),1.05(t,J=7.2Hz,3H);13C NMR(101MHz,DMSO-d 6)δ 168.98,48.08,33.54,17.16,14.43。
氯化(R)-1-側氧基-1-((3,3,3-三氟丙基)胺基)丙-2-胺鎓
標題分子以灰白色固體狀分離:mp 128-131℃;1H NMR(300MHz,DMSO-d 6)δ 8.62(bs,1H),8.10(bs,3H),3.82-3.79(m,1H),3.50-3.38(m,2H),2.50-2.37(m,2H),1.34(d,J=6.9Hz,3H)。
氯化(R)-1-側氧基-1-((2,2,2-三氟乙基)胺基)戊-2-胺鎓
標題分子以白色固體狀分離:mp 204-210℃;1H NMR(400MHz,CD3OD)δ 4.17-4.00(m,1H),3.98-3.69(m,2H),1.83(dt,J=15.0,7.5Hz,2H),1.50-1.35(m,2H),0.99(t,J=7.3Hz,3H);19F NMR(376MHz,CD3OD)δ
-73.90;13C NMR(101MHz,CD3OD)δ 170.97,125.72(q,J=277.9Hz),54.37,41.30(q,J=34.7Hz),34.65,19.00,13.94。
在室溫下向經攪拌之(R)-1-側氧基-1-(2,2,2-三氟乙基胺基)丙-2-基胺基甲酸第三丁酯(100mg,0.37mmol)於CH2Cl2(10mL)中之溶液中添加P2S5(24mg,0.11mmol)及六甲基二矽氧烷(HMDO)(0.13mL,0.59mmol),且將混合物回流3h。將反應混合物冷卻至室溫,且再添加一份P2S5(24mg,0.11mmol),且將所得混合物回流18h。蒸發揮發性物質,將戊烷(25mL)添加至殘餘物中且攪拌10-15min。傾析戊烷層,在真空中濃縮,且殘餘物依序用戊烷及CH2Cl2溶離而通過短二氧化矽墊,得到呈無色液體狀之標題化合物(30mg,30%):1H NMR(400MHz,DMSO-d 6)δ 10.27(t,J=5.4Hz,1H),7.00(d,J=6.8Hz,1H),4.57-4.35(m,3H),1.32(s,9H),1.25(d,J=7.6Hz,3H);ESIMS m/z 286.2([M+H]+);IR(薄膜)3233,1683,1257cm-1。
向經攪拌之(R)-1-硫酮基-1-(2,2,2-三氟乙基胺基)
丙-2-基胺基甲酸第三丁酯(200mg,0.69mmol)於CH2Cl2(5mL)中之溶液中逐滴添加TFA(0.5mL),且將反應混合物攪拌18h。蒸發揮發性物質,且殘餘物用戊烷濕磨,得到呈無色膠狀物之標題化合物(200mg),該標題化合物未經進一步純化即用於下一步驟:1H NMR(300MHz,DMSO-d 6)δ 10.99(bs,1H),8.23(bs,2H),4.62-4.55(m,2H),4.23-4.19(m,1H),1.43(d,J=8.4Hz,3H);ESIMS m/z 186.2([M+H]+);IR(薄膜)3445,2967,1168cm-1。
以下分子根據實例131中揭示之程序製造:
2,2,2-三氟乙酸(S)-1-側氧基-1-((2,2,2-三氟乙基)胺基)丁-2-胺鎓
標題分子以無色膠狀物分離:1H NMR(300MHz,DMSO-d 6)δ 9.12(t,J=5.7Hz,1H),8.19(bs,2H),4.14-3.93(m,2H),3.80(t,J=6.0Hz,1H),1.81-1.71(m,2H),0.88(t,J=7.2Hz,3H);ESIMS m/z 185.00([M+H]+);IR(薄膜)3459,1674,1169cm-1。
如實例15中所述製備標題分子。非對映體對藉由對掌性HPLC使用Chiralpak® IA(4.6×250mm)5μm管柱使用配於己烷之0.1% TFA及異丙醇作為移動相(等度70:30)以流速1.0mL/min在環境溫度下分離。非對映異構體F10在4.55min之滯留時間下收集,且具有[α]D 30=+35.6(c,0.5%於CH2Cl2中)之旋光度。非對映異構體F11在8.71min下收集,且具有[α]D 30=-82.0(c,0.5%於CH2Cl2中)之旋光度。此等分子之表徵資料列於表2中。
如實例15中所述製備標題分子。非對映體對藉由對掌性HPLC使用Chiralpak® IA(4.6×250mm)5μm管柱使用配於己烷之0.1% TFA及異丙醇作為移動相(等度70:30)以流速1.0mL/min在環境溫度下分離。非對映異構體F12在5.62min之滯留時間下收集,且具有[α]D 30=+59.4(c,1%於CH2Cl2中)之旋光度。非對映異構體F13在8.85min下收集,且具有[α]D 30=-44.0(c,1%於CH2Cl2中)之旋光度。此等分
子之表徵資料列於表2中。
以下分子根據實例133中揭示之程序製備:
N-((R)-1-側氧基-1-((2,2,2-三氟乙基)胺基)丙-2-基)-4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲醯胺(F20A及F20B)
非對映異構體F20A(異構體1)在4.13min之滯留時間下收集,且具有[α]D 25=+49.2(c,1.0%於CH2Cl2中)之旋光度。非對映異構體F20B在4.88min下收集,且具有[α]D 25=-38.8(c,1.0%於CH2Cl2中)之旋光度。此等分子之表徵資料列於表2中。
F20A及F20B立體化學指定 將F20A及F20B溶解於CDCl3中,且置放於具有BaF2窗之100μm路徑長度單元中。IR及振動圓二色性(VCD)光譜記錄在裝備有二重PEM附件之具有4cm-1解析度之IR-2XTM VCD分光計(BioTools,Inc.)上。在於1400cm-1下最佳化之儀器上持續21h獲取樣品及CDCl3光譜。收集減去溶劑之IR及VCD光譜。
理論計算:具有R,R-組態及S,R-組態之F20用Maestro(Schrodinger,LLC.New York,NY)建構。構形搜尋用MacroModel(Schrodinger,LLC.New York,NY)用MMFF94x力場進行,產生低能構象異構體。單點計算(SPE)、幾何學、頻率以及IR及VCD計算在DFT層面
(B3LYP/lacvp**)下在Jaguar(Schrodinger,LLC.New York,NY)中進行。將比例因子0.96應用於頻率計算。分析:針對具有R,R-組態及S,R-組態之F20,選擇用MacroModel產生之前100個低能構象異構體以用於DFT SPE計算。此等計算分別產生8個及4個構象異構體,該等構象異構體之能量比對於R,R-組態及S,R-組態之最低能量構象異構體高1kcal/mol內。在此等構象異構體上進行頻率計算以測定IR及VCD光譜。將此等構象異構體之波耳茲曼(Boltzmann)加權之IR及VCD光譜與所觀察之IR及VCD光譜相比。基於所觀察與所計算之光譜之間的VCD圖案之整體一致,將F20Ais之絕對組態指定為R,R-組態。該指定利用CompareVOA程式(BioTools)評估。基於包括針對不同對掌性結構之105個前述正確指定之資料庫,該指定之置信水準為88%。然而,針對F20B所觀察之光譜並不與所計算之S,R-組態之光譜完全一致,其置信水準為65%。但考慮到化合物僅具有一個對掌性中心,兩個可能的組態及F20A為R,R-組態,F20B可在較高置信度情況下指定為S,R-組態。
在室溫下向經攪拌之(E)-2-甲基-N-(2-甲基-1-側
氧基-1-(2,2,2-三氟乙基胺基)丙-2-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺(400mg,0.68mmol)於CH2Cl2(50mL)中之溶液中添加P2S5(75mg,0.34mmol)及HMDO(0.25mL,1.12mmol),且將混合物回流3h。將反應混合物冷卻至室溫,且再添加一份P2S5(75mg,0.34mmol),且將所得混合物回流18h。蒸發揮發性物質,且殘餘物藉由製備型TLC純化,得到呈淺黃色膠狀物之標題化合物(47mg,11%)。此分子之表徵資料列於表2中。
向含(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(200mg,0.409mmol)之MeCN(5mL)中添加水合1H-苯并[d][1,2,3]三唑-1-醇(63mg,0.411mmol)、HBTU(155mg,0.409mmol)、N-(2,2,2-三氟乙基)1-胺基-2-甲基-丙烷甲醯胺鹽酸鹽(180mg,0.816mmol)及二異丙基乙胺(0.24mL,1.38mmol)。24h後,在真空中濃縮該物質。粗產物藉由使粗反應混合物流過二氧化矽玻璃料且用配於己烷之EtOAc(1:2)溶離來純化。所回收之物質藉由二氧化矽
中壓層析用配於己烷之EtOAc作為溶離劑來進一步純化,得到呈白色泡沫狀之標題物(147mg,55%)。此分子之表徵資料列於表2中。
將異丙基氯化鎂氯化鋰複合物(22.0mL,28.02mmol)逐滴添加至在-5℃下之經攪拌之5-溴-1,3-二氟-2-甲氧基苯(5.0g,22.42mmol)於THF(100mL)中之溶液中,且將反應混合物在相同溫度下攪拌30min。逐滴添加三氟乙酸甲酯(3.67g,28.69mmol),且將反應混合物在環境溫度下攪拌2h。添加2N HCl溶液(200mL)以淬滅反應物,且其接著用乙醚萃取。合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾且濃縮,得到呈黃色液體狀之標題化合物(5.4g,粗物質)。該物質未經進一步純化即用於下一步驟。1H NMR(400MHz,CDCl3)δ 7.68-7.60(m,2H)4.19(s,3H);ESIMS m/z 240.1([M]+)。
以下分子根據實例136中揭示之程序製備:
2,6-二氟-4-(2,2,2-三氟乙醯基)苯甲腈
1H NMR(400MHz,CDCl3)δ 7.45(d,J=8.4Hz,1H),
7.37(d,J=8.4Hz,1H)。;EIMS m/z 235.1([M]+)。
步驟1:(2R)-2-(4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)苯甲醯胺基)丙酸第三丁酯:標題化合物根據實例15中概述之程序製備:1HNMR(400MHz,DMSO d6)δ 8.73(d,J=6.8Hz,1H),7.92-7.90(m,3H),7.61(d,J=7.2Hz,1H),7.36(d,J=7.6Hz,1H),6.99(dd,J=15.2,9.2Hz,1H),6.77(d,J=15.2Hz,1H),4.85-4.80(m,1H),4.30-4.26(m,1H),1.43(s,9H),1.33(d,J=6.8Hz,3H);ESIMS m/z 601.9([M-H]-);IR(KBr)3414,1732,1661,1170,748cm-1。
步驟2:(2R)-(4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)苯甲醯胺基)丙酸:在0℃下將TFA(1mL)添加至經攪拌之2-(2-溴-4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)丙酸第三丁酯(1.0g,1.63mmol)於CH2Cl2(20mL)中之溶液中,且將反應混合物在環境溫度下攪拌18h。在真空下蒸發揮發性物質,且殘餘物用戊烷濕磨,得到呈棕色固體狀之標題化合物(0.65g,67%):1HNMR(400MHz,DMSO-d 6)δ 12.60(bs,
1H),8.82(d,J=8.0Hz,1H),7.99(s,1H),7.92-7.89(m,3H),7.51(d,J=8.0Hz,1H),7.08(dd,J=15.6,8.8Hz,1H),6.88(d,J=15.6Hz,1H),4.88-4.83(m,1H),4.41-4.34(m,1H),1.34(d,J=7.2Hz,3H);ESIMS:m/z 545.7([M-H]+);IR(KBr)3410,3281,2928,1728,1172,744cm-1。
步驟3. (E)-N-(1-((2-氟乙基)胺基)-1-側氧基丙-2-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)-2-(三氟甲基)苯甲醯胺(P1618):在環境溫度下將DIPEA(0.60mL,1.08mmol)、PyBOP(180mg,0.36mmol)、2-(4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)-2-(三氟甲基)苯甲醯胺基)丙酸(35mg,0.36mmol)添加至經攪拌之化合物1(200mg,0.36mmol)於CH2Cl2(10mL)中之溶液中,且將反應混合物攪拌18h。反應混合物用CH2Cl2稀釋,依序用1N HCl以及NaHCO3飽和溶液、水及鹽水洗滌。有機相經乾燥(Na2SO4),過濾,濃縮,且殘餘物藉由二氧化矽管柱層析(100-200篩目)用配於石油醚之10% EtOAc溶離來純化,得到呈棕色固體狀之標題化合物(85mg,39%)。
以下分子根據實例137之步驟1中揭示之程序製備:
2-(2-溴-4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)丙酸第三丁酯
1H NMR(400MHz,DMSO-d 6):δ 8.82(d,J=7.6Hz,1H),7.99(s,1H),7.91-7.90(m,3H),7.50(d,J=7.6Hz,1H),7.07(dd,J=16.0,8.8Hz,1H),6.88(d,J=15.2Hz,1H),4.88-4.83(m,1H),4.31-4.27(m,1H),1.42(s,9H),1.32(d,J=7.6Hz,3H);ESIMS m/z 611.7([M-H]-);IR(KBr)3296,2932,1732,1162,743,556cm-1。
(E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)乙酸第三丁酯
以淺黃色固體狀分離(620mg,72%)。1H NMR(400MHz,DMSO-d6)δ 8.77(t,J=6.0Hz,1H),7.93-7.91(m,3H),7.62(d,J=6.8Hz,1H),7.39(d,J=8.0Hz,1H),7.00(dd,J=15.6,9.2Hz,1H),6.77(d,J=16.0Hz,1H),4.86-4.81(m,1H),3.86-3.85(m,2H),1.33(s,9H)。ESIMS m/z 599.87([M+H]+)。
以下分子根據實例137之步驟2中揭示之程序製備:
2-(2-溴-4-((E)-4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)丙酸
1HNMR(400MHz,DMSO-d 6):δ 12.62(bs,1H),8.73(d,J=9.6Hz,1H),7.93-7.91(m,3H),7.61(d,J=8.1Hz,1H),7.37(d,J=7.8Hz,1H),7.01(dd,J=15.6,9.0Hz,1H),6.78(d,J=15.9Hz,1H),4.89-4.79(m,1H),4.42-4.32(m,1H),1.36(d,J=7.2Hz,3H);ESIMS:m/z 558.0([M+H]+);IR(KBr)3418,1650,1115,747,560cm-1。
(E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲醯胺基)乙酸
以灰白色固體狀分離(550mg,97%)。1H NMR(300MHz,DMSO-d6)δ 12.56(bs,1H),8.73(t,J=5.4Hz,1H),7.93-7.91(m,3H),7.62(d,J=9.3Hz,1H),7.40(d,J=8.1Hz,1H),7.01(dd,J=15.9,9.0Hz,1H),6.78(d,J=15.9Hz,1H),4.89-4.80(m,1H),3.90-3.88(m,2H)。ESIMS m/z 541.82([M-H]-)。
步驟1. 4-溴-2-氯-5-甲氧基苯甲酸甲酯:裝備有
磁性攪拌棒之25mL圓底燒瓶饋有4-溴-2-氯-5-甲氧基苯甲酸(JACS,1963,730-2;1.25g,4.72mmol)、20% MeOH/EtOAc(25mL),且於冰-水浴中冷卻。經由加料漏斗逐滴添加三甲基矽烷基重氮甲烷(TMSCHN2 2M於己烷中,2.6mL,5.20mmol)。將反應物繼續攪拌1h,接著將其濃縮,得到呈白色固體狀之標題化合物(1.31g,100%):mp 78-79℃;1H NMR(400MHz,CDCl3)δ 7.65(s,1H),7.36(s,1H),3.94(s,3H),3.93(s,3H);EIMS m/z 280([M]+)。
步驟2. 2-氯-5-甲氧基-4-乙烯基苯甲酸:25mL圓底燒瓶饋有4-溴-2-氯-5-甲氧基苯甲酸甲酯(640mg,2.29mmol)、K2CO3(665mg,4.81mmol)、三氟(乙烯基)硼酸鉀(920mg,6.87mmol)、PdCl2(dppf)(84mg,0.11mmol)及無水DMSO(15mL)且在80℃下攪拌2h。使反應物冷卻,添加水(150mL),且接著用Et2O萃取數次。有機層用鹽水洗滌,經MgSO4乾燥,過濾且濃縮,得到棕色殘餘物。粗產物經由急驟層析用配於己烷之15% Et2O溶離來純化,得到呈黃色油狀物之2-氯-5-甲氧基-4-乙烯基苯甲酸甲酯(440mg,85%)。向含有2-氯-5-甲氧基-4-乙烯基苯甲酸甲酯(440mg,1.94mmol)及MeOH(10mL)之25mL圓底燒瓶中添加1N NaOH(2mL,2.04mmol),且將反應物在環境溫度下攪拌18h。濃縮反應混合物,得到固體殘餘物。將殘餘物溶解於水中且用配於己烷之50% Et2O萃取1×。水層用2N HCl製成酸性,且用CH2Cl2萃取2×,經MgSO4乾燥,過濾且濃縮,得到呈白色固體狀之標題化合物(0.39g,94%):1H NMR(400
MHz,CDCl3)δ 7.54(d,J=0.5Hz,1H),7.52(s,1H),6.98(ddd,J=17.7,11.2,0.6Hz,1H),5.87(dd,J=17.7,1.1Hz,1H),5.45(dd,J=11.2,1.1Hz,1H),3.90(s,3H)。
步驟3. (E)-2-氯-5-甲氧基-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸:50mL 3頸圓底燒瓶饋有2-氯-5-甲氧基-4-乙烯基苯甲酸(390mg,1.84mmol))、5-(1-溴-2,2,2-三氟乙基)-1,2,3-三氯苯(754mg,2.20mmol)及無水N-甲基吡咯啶酮(10mL)。將氮氣鼓泡至反應混合物中持續15min。此後,添加2,2'-聯吡啶(57.3mg,0.37mmol)及CuBr(11.7mg,0.18mmol),且將反應混合物在150℃下攪拌1h。使反應混合物冷卻,添加水(300mL)且用Et2O萃取數次。有機層用水反覆洗滌,經MgSO4乾燥,過濾且濃縮,得到呈淡棕色泡沫狀之標題化合物(870mg,100%)。根據LC/MS,此物質為95%純:ESIMS m/z 473([M-H]-)。此物質未經進一步純化即使用。
步驟4. (E)-2-氯-5-甲氧基-N-(2-側氧基-2-((2,2,2-三氟乙基)胺基)乙基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺:50mL圓底燒瓶饋有(E)-2-氯-5-甲氧基-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸(780mg,1.65mmol))、二(1H-咪唑-1-基)甲酮(267mg,1.65mmol)及無水THF(30mL)。將所得混合物在回流下加熱直至其停止放出氣體。一次性添加2-胺基-N-(2,2,2-三氟乙基)乙醯胺鹽酸鹽(257mg,1.65mmol),且將反應混合物在回流下繼續攪拌18h。將反應混合物濃縮至乾燥,且將
殘餘物吸收於Et2O(50mL)及0.1N HCl(10mL)中。分離各層。水層用Et2O萃取2×。Et2O層經合併,且用NaHCO3水溶液洗滌1×,用鹽水洗滌1×,經MgSO4乾燥,過濾且濃縮,得到棕色油狀物。粗產物經由急驟層析用30-40% EtOAc/己烷溶離來純化,得到呈灰白色泡沫狀之標題化合物(280mg,28%):1H NMR(400MHz,CDCl3)δ 7.45(s,1H),7.41(s,2H),7.29(s,1H),7.28(s,1H),6.84(m,2H),6.43(dd,J=16.0,8.3Hz,1H),4.25(d,J=5.4Hz,2H),4.10(m,1H),3.97(qd,J=9.0,6.4Hz,2H),3.87(s,3H);ESIMS m/z 613.1([M+H]+)。
步驟5. (E)-2-氯-5-羥基-N-(2-側氧基-2-((2,2,2-三氟乙基)胺基)乙基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺:25mL圓底燒瓶饋有(E)-2-氯-5-甲氧基-N-(2-側氧基-2-((2,2,2-三氟乙基)胺基)乙基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺(57mg,0.093mmol)及CH2Cl2(3mL)。將反應混合物冷卻至-78℃,且經由注射器緩慢添加三溴化硼(BBr3,1.0M CH2Cl2溶液,0.33mL,0.326mmol)。使反應物溫至環境溫度且攪拌18h。在環境溫度下再添加0.3-0.4mL BBr3,且繼續攪拌3h。將反應混合物添加至NaHCO3水溶液中且用CH2Cl2萃取3×。CH2Cl2層經合併且經MgSO4乾燥,過濾且濃縮,得到油狀物。粗物質經由急驟層析用配於己烷之50% EtOAc溶離來純化,得到呈白色固體狀之標題化合物(18mg,33%):mp 190℃(度);1H NMR(400MHz,CDCl3)δ 9.81(s,1H),8.06
(d,J=7.0Hz,1H),7.71(m,1H),7.44(d,J=2.8Hz,2H),7.37(s,1H),7.20(s,1H),6.82(d,J=15.9Hz,1H),6.50(m,1H),4.14(m,3H),3.89(m,2H);ESIMS m/z 599([M+H]+)。
在氮氣氛圍下經由加料漏斗向經磁力攪拌之4-溴-1,2-二氯苯(5.64g,24.98mmol)於無水Et2O(109mL)中之溶液中添加n-BuLi(10.86mL,24.98mmol)。將反應混合物在-78℃下攪拌30min,經15min逐滴添加2,2-二氟丙酸乙酯(3.0g,21.7mmol)於Et2O(10mL)中之溶液且使其攪拌1h。接著用1N HCl(4mL)小心地淬滅反應物,且使其溫至23℃。溶液用Et2O稀釋且用水洗滌。合併之有機層經Na2SO4乾燥,在減壓下濃縮,且所得物質經由急驟管柱層析使用100%己烷至5%丙酮/95%己烷作為溶離劑來純化。在減壓下濃縮相關溶離份,得到呈無色油狀物之標題化合物(3.89g,71%):1H NMR(400MHz,CDCl3)δ 8.21-8.18(m,1H),7.99-7.93(m,1H),7.59(dd,J=8.4,4.2Hz,1H),1.89(t,J=19.6Hz,3H);19F NMR(376MHz,CDCl3)δ -92.08--93.21(m);EISMS m/z 240([M-H]+)。
向經攪拌之(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)苯甲酸(600mg,1.23mmol)於無水甲苯(10mL)中之溶液中添加三丁基(乙烯基)錫烷(470mg,1.48mmol),且混合物用氬氣脫氣15min。添加Pd(PPh3)4(72mg,0.06mmol),且將反應混合物回流2h。使反應混合物回至環境溫度,添加水且用EtOAc萃取混合物。有機層用2N HCl及鹽水洗滌,乾燥(Na2SO4),過濾且濃縮。殘餘物藉由二氧化矽管柱層析用配於石油醚之30% EtOAc溶離來純化,得到呈棕色固體狀之標題化合物(295mg,55%):1H NMR(300MHz,DMSO-d 6)δ 13.05(bs,1H),7.91(s,2H),7.81-7.75(m,2H),7.59(d,J=8.1Hz,1H),7.48(dd,J=17.4,10.8Hz,1H),7.03(dd,J=15.9,8.7Hz,1H),6.84(d,J=15.6Hz,1H),5.88(d,J=16.5Hz,1H),5.39(d,J=12.3Hz,1H),4.89-4.82(m,1H);ESIMS m/z 432.18([M-H]-);IR(薄膜)3418,1689,1114,747cm-1。
Per Buchwald等人;JACS,2002,124,14844-14845,將碘化鉀(KI,273mg,1.64mmol)、CuI(31mg,0.16mmol)及反-N,N'-二甲基環己烷-1,2-二胺(催化量)添加至(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯基)
苯甲酸(400mg,0.82mmol)於1,4-二噁烷(8mL)中之溶液中。將混合物在Ace壓力管中在100℃下加熱3h。使反應混合物回至環境溫度,且經由Celite®墊過濾。濃縮濾液,且殘餘物用EtOAc稀釋且依序用1N HCl及鹽水洗滌。將有機層乾燥(Na2SO4),過濾且濃縮。殘餘物藉由二氧化矽管柱層析用配於石油醚之25% EtOAc溶離來純化,得到呈棕色半固體狀之標題化合物(240mg,55%):1H NMR(400MHz,DMSO-d 6)δ 13.3(bs,1H),8.21(s,1H),7.91(s,2H),7.71-7.64(m,2H),7.01(dd,J=15.6,9.2Hz,1H),6.75(d,J=15.6Hz,1H),4.85-4.81(m,1H);ESIMS m/z 532.8([M-H]-);IR(薄膜)3436,1699,1113,750cm-1。
步驟1. (E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺基)-2-甲基丙酸:裝備有磁性攪拌棒及回流冷凝器之25mL圓底燒瓶饋有(E)-2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲酸(400mg,0.82mmol)及1,2-二氯乙烷(DCE)(5mL)。一次性利落地添加亞硫醯氯(0.12mL,1.64mmol),且將所得反應混合物在回流下加熱2h。此後,使反應混合物冷卻且濃縮,得到粗酸氯化
物,該粗酸氯化物未經進一步純化即使用。向含有NaHCO3(68.8mg,0.82mmol)、2-胺基-2-甲基丙酸(84mg,0.82mmol)及溴化十二烷基三甲基銨(2.52mg,8.19μmol)於10mL THF中之溶液中添加至含酸氯化物之THF(1mL)中。將所得混合物在回流下加熱18h。使反應混合物冷卻且將其添加至水中,用0.1N HCl製成酸性,用Et2O萃取(3×),用鹽水洗滌(1×),經MgSO4乾燥,過濾且蒸發,得到呈淡棕色泡沫狀之標題化合物(400mg,85%):1H NMR(400MHz,CDCl3)δ 7.60(d,J=1.6Hz,1H),7.59(d,J=8.0Hz,1H),7.40(s,2H),7.37(dd,J=8.1,1.6Hz,1H),6.63(s,1H),6.53(d,J=15.9Hz,1H),6.38(dd,J=15.9,7.9Hz,1H),4.10(p,J=8.3Hz,1H),1.73(s,6H)。此物質未經進一步純化即使用。
步驟2. (E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)-4,4-二甲基噁唑-5(4H)-酮:25mL圓底燒瓶饋有(E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺基)-2-甲基丙酸(400mg,0.70mmol)、CH2Cl2(10mL)且在0℃下攪拌。一次性添加呈固體狀之EDC.HCl(134mg,0.70mmol),且使反應混合物溫至環境溫度且繼續攪拌1h。反應物用CH2Cl2稀釋,用鹽水洗滌,經MgSO4乾燥,過濾且蒸發,得到深色油狀物。粗產物經由急驟層析用配於CH2Cl2之50%己烷溶離來純化,得到呈灰白色泡沫狀之標題化合物(220mg,57):1H NMR(400MHz,CDCl3)δ 7.76(d,J=8.1Hz,1H),7.73(d,J=1.6
Hz,1H),7.42(d,J=7.8Hz,3H),6.56(d,J=15.9Hz,1H),6.45(dd,J=15.9,7.7Hz,1H),4.12(p,J=8.5Hz,1H),1.57(s,6H);19F NMR(376MHz,CDCl3)δ -68.55;ESIMS m/z 554([M-H]-)。
步驟3. (E)-2-溴-N-(2-甲基-1-(新戊基胺基)-1-側氧基丙-2-基)-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯甲醯胺:10mL圓底燒瓶饋有(E)-2-(2-溴-4-(4,4,4-三氟-3-(3,4,5-三氯苯基)丁-1-烯-1-基)苯基)-4,4-二甲基噁唑-5(4H)-酮(90mg,0.16mmol)及CH2Cl2(2mL)。經由移液管利落地添加2,2-二甲基丙-1-胺(28.2mg,0.324mmol),且將反應物在環境溫度下攪拌18h。蒸發反應混合物,得到油狀物。粗產物經由急驟層析用配於己烷之20% EtOAc/溶離來純化,得到呈白色泡沫狀之標題化合物(90mg,86%):1H NMR(400MHz,CDCl3)δ 7.60(d,J=1.6Hz,1H),7.51(d,J=8.0Hz,1H),7.40(s,2H),7.36(dd,J=8.1,1.6Hz,1H),6.66(d,J=10.0Hz,2H),6.53(d,J=15.9Hz,1H),6.38(dd,J=15.9,7.8Hz,1H),4.11(m,1H),3.12(d,J=6.2Hz,2H),1.72(s,6H),0.93(s,9H);19F NMR(376MHz,CDCl3)δ -68.62;ESIMS m/z 643.19([M+H]+)。
步驟1. 4-胺基-3,5-二溴苯甲酸甲酯:在環境溫度下將濃H2SO4(1.35mL,25.48mmol)逐滴添加至經攪拌之4-
胺基-3,5-二溴苯甲酸(5.0g,16.99mmol)於MeOH(50mL)中之溶液中,且接著將反應混合物在80℃下攪拌8h。使反應混合物回至環境溫度,蒸發揮發性物質,且將冰冷的水添加至殘餘物中,且該殘餘物接著用EtOAc萃取。有機層依序用NaHCO3水溶液以及鹽水及水洗滌。溶液接著經乾燥(Na2SO4),過濾且濃縮,得到呈灰白色固體狀之標題化合物(5.0g,95%):1H NMR(300MHz,DMSO-d 6)δ 7.91(s,2H),6.20(bs,2H),3.78(s,3H);ESIMS m/z 307.0([M]+);IR(薄膜)3312,2953,1726,595cm-1。
步驟2. 3,5-二溴-4-氯苯甲酸甲酯:將含CuCl2(2.82g,21.0mmol)之MeCN(30mL)在80℃下攪拌30min。接著在相同溫度下向此混合物中逐滴添加亞硝酸第三丁酯(2.7mL,23mmol),且將混合物再攪拌10min。將含4-胺基-3,5-二溴苯甲酸甲酯(5.0g,16mmol)之MeCN(30mL)逐滴添加至反應混合物中,且接著在80℃下攪拌30min。使反應混合物回至環境溫度,且將氨水溶液(20mL)添加至反應混合物中且用石油醚萃取。有機層依序用鹽水及水洗滌,乾燥(Na2SO4),過濾且濃縮,得到呈灰白色固體狀之標題化合物(4.5g,84%)。1H NMR(300MHz,DMSO-d 6)δ 8.21(s,2H),3.94(s,3H);ESIMS m/z 326([M]+);IR(薄膜)1732,746cm-1。
步驟3. (3,5-二溴-4-氯苯基)甲醇:在0℃下將NaBH4(1.53g,40.65mmol)逐份添加至經攪拌之3,5-二溴-4-氯苯甲酸甲酯(4.45g,13.6mmol)於MeOH(50mL)中之溶液
中。接著將反應混合物在環境溫度下攪拌8h。蒸發揮發性物質,且殘餘物用CH2Cl2稀釋且依序用鹽水及水洗滌。有機層經乾燥(Na2SO4),過濾且濃縮,得到呈灰白色固體狀之標題化合物(3.3g,80%):1H NMR(300MHz,DMSO-d 6)δ 7.71(s,2H),5.49(bs,1H),4.48(d,J=4.5Hz,2H);ESIMS m/z 297.9([M]+);IR(薄膜)3460,747,534cm-1。
步驟4. 3,5-二溴-4-氯苯甲醛:在環境溫度下將氯鉻酸吡錠(PCC,3.44g,15.9mmol)一次性添加至經攪拌之(3,5-二溴-4-氯苯基)甲醇(3.2g,11.0mmol)於CHCl3(40mL)中之溶液中,且將反應混合物攪拌隔夜。反應混合物經由Celite®過濾,Celite®墊用CHCl3洗滌,且濃縮濾液,得到呈灰白色固體狀之標題化合物(2.0g,62%):mp 110-113℃;1H NMR(300MHz,DMSO-d 6)δ 9.93(s,1H),8.27(s,2H);ESIMS m/z 297.0([M]+)。
步驟1. 4-胺基-3,5-二氯苯甲酸甲酯:在0℃下將濃H2SO4(2.5mL,97.04mmol)逐滴添加至經攪拌之4-胺基-3,5-二氯苯甲酸(10.0g,48.54mmol)於MeOH(150mL)中之溶液中,且接著將反應混合物在80℃下攪拌8h。蒸發揮發性物質;將冰冷的水添加至殘餘物中,且該殘餘物接著用EtOAc萃取。合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾且在減壓下濃縮,得到呈白色固體狀之標題化合物(7.5
g,70%):1H NMR(300MHz,DMSO-d 6)δ 8.05(s,2H),3.96(s,3H);ESIMS m/z 282([M]+);IR(KBr):1733,762,514cm-1。
步驟2. 4-溴-3,5-二氯苯甲酸甲酯:將含CuBr2(7.5g,34.08mmol)之MeCN(50mL)在80℃下攪拌30min。在相同溫度下向此溶液中逐滴添加亞硝酸第三丁酯(6.5mL,54.55mmol),且將混合物再攪拌10min。將含4-胺基-3,5-二氯苯甲酸甲酯之MeCN(30mL)逐滴添加至反應混合物中,接著將該反應混合物在80℃下攪拌30min。使反應混合物回至環境溫度。添加氨水溶液(20mL)且用石油醚萃取。有機層依序用鹽水及水洗滌。有機溶液經乾燥(Na2SO4),過濾且濃縮,得到呈灰白色固體狀之標題化合物(7.5g,77%):1H NMR(300MHz,DMSO-d 6)δ 8.02(s,2H),3.94(s,3H);ESIMS m/z 282([M]+);IR(薄膜)1733,762,514cm-1。
步驟3. (4-溴-3,5-二氯苯基)甲醇:在-78℃下將DIBAL-H(1M於甲苯中,66mL,及66.0mmol)逐滴添加至經攪拌之4-溴-3,5-二氯苯甲酸甲酯(7.5g,26.0mmol)於THF(50mL)中之溶液中。使反應混合物回至環境溫度且攪拌6h。將反應混合物傾注至冰-水中且用CH2Cl2萃取。有機層依序用鹽水及水洗滌,乾燥(Na2SO4),過濾且濃縮,得到呈灰白色固體狀之(4-溴-3,5-二氯苯基)甲醇及4-溴-3,5-二氯苯甲醛之混合物(6.0g),該混合物未經純化即用於下一步驟。
步驟4. 4-溴-3,5-二氯苯甲醛:在環境溫度下將PCC(7.5g,35.16mmol)一次性添加經攪拌之含有(4-溴-3,5-二氯苯基)甲醇及4-溴-3,5-二氯苯甲醛之混合物(6.0g)於CHCl3(40mL)中之溶液中,且將反應混合物攪拌隔夜。反應混合物經由celite過濾。celite墊用CHCl3洗滌。濃縮濾液,得到呈灰白色固體狀之標題化合物(3.5g,67%):mp 125-128℃;1H NMR(300MHz,DMSO-d 6)δ 9.96(s,1H),8.10(s,2H);ESIMS m/z 252([M]+)。
在環境溫度下將PdCl2(dppf)(37mg,0.046mmol)、磷酸鉀(1.93g,9.11mmol)及三乙基硼烷(1M於己烷中,0.45g,4.56mmol)添加至3-溴-5-氯-苯甲醛(1.0g,4.56mmol)於THF(20mL)中之溶液中,且將混合物回流12h。使反應混合物回至環境溫度,用EtOAc稀釋且用水洗滌。有機層經乾燥(Na2SO4),過濾,濃縮,且殘餘物藉由二氧化矽管柱層析(100-200篩目)用配於石油醚之2% EtOAc溶離來純化,得到呈淺黃色液體狀之標題化合物(330mg,41%):1H NMR(400MHz,DMSO-d 6)δ 9.97(s,1H),7.75(d,J=1.6Hz 1H),7.73(s,1H),7.65(s,1H),2.74-2.68(m,2H),1.23(t,J=7.6Hz,3H);ESIMS m/z 168.0([M]+);IR(薄膜)3071,1699,692cm-1。
步驟1. (E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-硝基苯甲酸乙酯:在環境溫度下將5-(1-溴-2,2,2-三氟乙基)-1,3-二氯-2-氟苯(3.5g,10.8mmol)、CuCl(54mg,0.54mmol)及2,2-聯吡啶(169mg,1.08mmol)添加至經攪拌之2-硝基-4-乙烯基苯甲酸乙酯(1.2g,5.42mmol)於1,2-二氯苯(12mL)中之溶液中,且接著將混合物在180℃下攪拌18h。將反應混合物接著冷卻至環境溫度,吸附在矽膠上且藉由管柱層析用配於石油醚之10% EtOAc溶離來純化,得到呈棕色液體狀之標題化合物(1.3g,53%):1H NMR(DMSO-d 6,300MHz)δ 8.31(s,1H),8.02-7.95(m,1H),7.88-7.85(m,3H),7.20(dd,J=15.9,9.3Hz,1H),6.91(d,J=15.6Hz,1H),4.91-4.85(m,1H),4.34-4.27(m,2H),1.27(t,J=6.6Hz,3H);ESIMS m/z 463.8([M-H]-);IR(KBr)3439,2985,1731,1251cm-1。
步驟2. (E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-硝基苯甲酸:在0℃下將濃HCl(16.0mL)逐滴添加經攪拌之(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-硝基苯甲酸乙酯(800mg,1.72mmol)於1,4-二噁烷
(8.0mL)中之溶液中,且將反應混合物回流36h。蒸發揮發性物質;殘餘物用EtOAc稀釋且用鹽水及水洗滌。有機層經乾燥(Na2SO4),過濾,濃縮,且殘餘物藉由二氧化矽管柱層析(100-200篩目)用配於石油醚之30% EtOAc溶離來純化,得到呈黃色固體狀之標題化合物(390mg,52%):1H NMR(400MHz,DMSO-d6)δ 13.9(bs,1H),8.22(s,1H),7.93-7.91(m,1H),7.86-7.84(m,3H),7.16(dd,J=15.6,9.2Hz,1H),6.89(d,J=15.6Hz,1H),4.89-4.85(m,1H)。ESIMS m/z 435.9([M-H]-);IR(KBr)3445,2924,1708,1541,817cm-1。
步驟3. (E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-硝基-N-(2-側氧基-2-(2,2,2-三氟乙基胺基)乙基)苯甲醯胺:將2-胺基-N-(2,2,2-三氟乙基)乙醯胺鹽酸鹽(96mg,0.35mmol)、PyBOP(165mg,0.32mmol)及DIPEA(0.1mL,0.57mmol)添加至經攪拌之(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-硝基苯甲酸(130mg,0.29mmol)於CH2Cl2(3mL)中之溶液中,且將反應混合物在環境溫度下攪拌8h。將水添加至反應混合物中且用CH2Cl2萃取。有機層用鹽水洗滌,乾燥(Na2SO4),過濾,濃縮,且殘餘物藉由二氧化矽管柱層析(100-200篩目)用配於石油醚之30% EtOAc溶離來純化,得到呈黃色固體狀之標題化合物(120mg,74%):1H NMR(300MHz,DMSO-d 6)δ 9.04(t,J=5.7Hz,1H),8.60(t,J=6.0Hz,1H),8.25(s,1H),7.97-7.94(m,1H),7.87(d,J=6.3Hz,2H),7.69(d,J=7.5
Hz,1H),7.15(dd,J=15.9,9.3Hz,1H),6.89(d,J=15.9Hz,1H),4.88-4.83(m,1H),3.98-3.89(m,4H);ESIMS m/z 575.87([M+H]+);IR(KBr)3430,2925,1663,1168,832cm-1。
步驟4. (E)-2-胺基-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-N-(2-側氧基-2-(2,2,2-三氟乙基胺基)乙基)苯甲醯胺:在環境溫度下將鐵粉(81.8mg,1.46mmol)及NH4Cl(104mg,1.94mmol)添加至經攪拌之(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-硝基-N-(2-側氧基-2-(2,2,2-三氟乙基胺基)乙基)苯甲醯胺(280mg,0.486mmol)於EtOH:水(6mL,1:1)中之溶液中,且將混合物在回流下攪拌90min。將反應混合物冷卻至環境溫度且經由celite過濾。濃縮濾液,且將殘餘物溶解於EtOAc中,且用NaHCO3飽和溶液、鹽水及水洗滌。有機層經乾燥(Na2SO4),過濾,濃縮,且殘餘物藉由二氧化矽管柱層析(10-200篩目)用配於石油醚之35% EtOAc溶離來純化,得到呈黃色固體狀之標題化合物(215mg,81%)。
在環境溫度下將DIPEA(0.20mL,1.26mmol)、
PyBOP(245mg,0.47mmol)及2-胺基-N-(2,2,2-三氟乙基)乙醯胺(90mg,0.47mmol)添加至經攪拌之(E)-2-溴-4-(3-(3,5-二氯-4-羥基苯基)-4,4,4-三氟丁-1-烯基)苯甲酸(200mg,0.42mmol,66%純)於CH2Cl2(5mL)中之溶液中。接著將所得混合物攪拌12h。反應混合物用CH2Cl2稀釋,依序用1N HCl以及碳酸氫鈉溶液、鹽水溶液及水洗滌。有機層經乾燥(Na2SO4),過濾,在真空下濃縮。殘餘物藉由二氧化矽管柱層析(100-200篩目)用配於石油醚之30% EtOAc溶離來純化,得到呈淡綠色固體狀之標題化合物(130mg,52%)。
饋有(R)-(3-甲基-1-側氧基-1-((2,2,2-三氟乙基)胺基)-丁-2-基)胺基甲酸苯甲酯(4.95g,14.9mmol)於100mL EtOAc及25mL EtOH之巴爾振盪燒瓶(Parr shaker flask)用175mg 10% Pd/C處理。將混合物置放在40psi氫氣下且振盪6h。再將65mg 10% Pd/C添加至反應混合物中,接著將該反應混合物置放在40psi氫氣下且振盪3.5h。反應溶液經由celite墊過濾,在真空中濃縮且藉由昇華(75℃至85℃,200-230毫巴)純化,得到呈白色固體狀之標題化合物(1.92g,65%):mp 43-47℃;1H NMR(400MHz,CDCl3)δ 8.04-7.74(m,1H),3.92(ddd,J=16.0,9.3,6.8Hz,1H),3.84-3.60(m,1H),3.23(d,J=3.8Hz,1H),2.23(ddd,J=10.7,
7.0,3.5Hz,1H),0.92(d,J=7.0Hz,3H),0.75(d,J=6.9Hz,3H);19F NMR(376MHz,CDCl3)δ -72.70。
在環境溫度下將過硫酸氫鉀(320mg,0.50mmol)添加至經攪拌之(E)-4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟丁-1-烯基)-2-(甲基硫基)-N-(2-側氧基-2-(2,2,2-三氟乙基胺基)乙基)苯甲醯胺(150mg,0.25mmol)於丙酮-水(10mL,1:1)中之溶液中,且將反應混合物攪拌18h。反應混合物接著用CH2Cl2萃取。有機層用鹽水及水洗滌,乾燥(Na2SO4),過濾,濃縮,且殘餘物用戊烷-Et2O(1:1)濕磨,得到呈灰白色固體狀之標題化合物(85mg,56%):1H NMR(300MHz,DMSO-d 6)δ 9.01(t,J=6.0,1H),8.37(t,J=6.4Hz,1H),8.08(s,1H),8.01-7.96(m,1H),7.88-7.86(m,2H),7.64(d,J=7.6Hz,1H),7.05(dd,J=16.4,8.8Hz,1H),6.91(d,J=15.6Hz,1H),4.87-4.80(m,1H),3.98-3.91(m,4H),3.38(s,3H);ESIMS m/z 608.85([M+H]+);IR(薄膜)337,416,721,164,768cm-1。
以下預示性分子可根據本申請案中揭示之程序製造:
以下預示性分子可根據本申請案中揭示之程序製造:
BAW幾乎無有效之寄生蟲、疾病或捕食者來減少其群體。BAW侵襲多種雜草、樹木、牧草、豆科植物及田間作物。在不同地方,出於經濟上之原因要考慮以下植物:蘆筍、棉花、玉米、大豆、菸草、苜蓿、甜菜、胡椒、番茄、馬鈴薯、洋蔥、豌豆、向日葵及柑橘以及其他植物。已知CEW侵襲玉米及番茄,而且其亦侵襲朝鮮薊、蘆筍、甘藍、香瓜、芥藍、豇豆、黃瓜、茄子、萵苣、菜豆、甜瓜、秋葵、豌豆、胡椒、馬鈴薯、南瓜(pumpkin)、四季豆、菠菜、南瓜(squash)、甘薯及西瓜以及其他植物。亦已知CEW對某些殺蟲劑具有抗性。亦已知CL對某些殺蟲劑具有抗性。因此,由於上述因素,控制此等害蟲為重要的。此外,控制此等害蟲之分子適用於控制其他害蟲。
使用以下實例中描述之程序針對BAW、CEW及CL測試本文件中揭示之某些分子。在報導結果時,使用「BAW及CEW及CL評級表」(參見表格部分)。
對BAW(甜菜夜蛾(Spodoptera exigua))進行之生物分析
使用128孔飼料托盤分析對BAW進行生物分析。將一至五隻第二齡期之BAW幼蟲置放在飼料托盤之各孔(3mL)中,且接著將其乾燥,各孔已經預先填充有1mL人工飼料,已向該飼料(向八個孔之各孔中)中施加50μg/cm2測試化合物(溶解在50μL之90:10丙酮-水混合物中)。托盤用透明的自黏型蓋子覆蓋並在25℃、14:10光-暗下保持五至七天。記錄各孔中之幼蟲之死亡率百分比;接著將八個孔中之活性求平均值。結果在標題為「表3:分析結果部分1」及「表4:分析結果部分2」(參見表格部分)之表中示出。
對CEW(穀實夜蛾(Helicoverpa zea))進行之生物分析
使用128孔飼料托盤分析對CEW進行生物分析。將一至五隻第二齡期之CEW幼蟲置放在飼料托盤之各孔(3mL)中,且接著將其乾燥,各孔已經預先填充有1mL人工飼料,已向該飼料(向八個孔之各孔中)中施加50μg/cm2測試化合物(溶解在50μL之90:10丙酮-水混合物中)。托盤用透明的自黏型蓋子覆蓋並在25℃、14:10光-暗下保持五至七天。記錄各孔中之幼蟲之死亡率百分比;接著將八個孔中之活性求平均值。結果在標題為「表3:分析結果部分1」(參見表格部分)之表中示出。
對CL(粉紋夜蛾(Trichoplusia ni))進行之生物分析
使用128孔飼料托盤分析對CL進行生物分析。將一至五隻第二齡期之CL幼蟲置放在飼料托盤之各孔(3mL)
中,且接著將其乾燥,各孔已經預先填充有1mL人工飼料,已向該飼料(向八個孔之各孔中)中施加50μg/cm2測試化合物(溶解在50μL之90:10丙酮-水混合物中)。托盤用透明的自黏型蓋子覆蓋並在25℃、14:10光-暗下保持五至七天。記錄各孔中之幼蟲之死亡率百分比;接著將八個孔中之活性求平均值。結果在標題為「表4:分析結果部分2」(參見表格部分)之表中示出。
GPA為桃樹最重要之蚜蟲害蟲,其導致生長減少、葉子枯萎及各種組織死亡。其亦為有害的,因為其作為將植物病毒(諸如馬鈴薯病毒Y及馬鈴薯卷葉病毒)運送至龍葵/馬鈴薯家族茄科(nightshade/potato family Solanaceae)之成員,及將各種嵌紋病毒運送至許多其他糧食作物之媒介。GPA侵襲諸如以下之植物:椰菜、牛蒡、甘藍、胡蘿蔔、花椰菜、蘿蔔(daikon)、茄子、青豆、萵苣、夏威夷果(macadamia)、番木瓜、胡椒、甘薯、番茄、水芥(watercress)及西葫蘆以及其他植物。GPA亦侵襲多種觀賞性作物,諸如康乃馨、菊花、白花甘藍(flowering white cabbage)、一品紅及玫瑰。GPA已發展出對多種殺蟲劑之抗性。
使用以下實例中描述之程序針對GPA測試本文件中揭示之某些分子。在報導結果時,使用「GPA評級表」(參見表格部分)。
將在3英吋盆中生長之具有2-3片小(3-5cm)真葉之甘藍幼苗用作測試基材。在化學品施用前一天,用20-50隻GPA(無翅成蟲及若蟲階段)侵害該等幼苗。針對各次處理使用四個具有個別幼苗之盆。將測試化合物(2mg)溶解於2mL丙酮/MeOH(1:1)溶劑中,形成1000ppm測試化合物之儲備溶液。將儲備溶液用含0.025% Tween 20之水稀釋5×,得到200ppm測試化合物之溶液。用手持抽吸型噴霧器將溶液噴至甘藍葉子之兩面直至徑流。用僅含有20體積%丙酮/MeOH(1:1)溶劑之稀釋劑對參考植物(溶劑檢查)進行噴霧。評級前,將經處理之植物在貯存室中在約25℃及環境相對濕度(RH)下置放三天。藉由在顯微鏡下計數每株植物上活蚜蟲之數目來進行評估。藉由使用如下所示之阿博特氏校正公式(Abbott's correction formula;W.S.Abbott,「A Method of Computing the Effectiveness of an Insecticide」J.Econ.Entomol.18(1925),第265-267頁)來量測控制百分比。
經校正之控制%=100×(X-Y)/X
其中X=溶劑檢查植物上之活蚜蟲數目,及Y=經處理植物上之活蚜蟲數目
結果在標題為「表3:分析結果部分1」及「表4:分析結果部分2」(參見表格部分)之表中示出。
殺蟲可接受之酸加成鹽、鹽衍生物、溶劑合物、酯衍生物、多晶型物、同位素及放射線核素
式I分子可調配成殺蟲可接受之酸加成鹽。藉助於非限制性實例,胺官能基可與以下酸形成鹽:鹽酸、氫溴酸、硫酸、磷酸、乙酸、苯甲酸、檸檬酸、丙二酸、水楊酸、蘋果酸、反丁烯二酸、乙二酸、丁二酸、酒石酸、乳酸、葡萄糖酸、抗壞血酸、順丁烯二酸、天冬胺酸、苯磺酸、甲磺酸、乙磺酸、羥基甲磺酸及羥基乙磺酸。此外,藉助於非限制性實例,酸官能基可形成鹽,包括衍生自鹼金屬或鹼土金屬之鹽以及衍生自氨及胺之鹽。較佳陽離子之實例包括鈉、鉀及鎂。
式I分子可調配成鹽衍生物。藉助於非限制性實例,可藉由使游離鹼與足量之所需酸接觸以產生鹽來製備鹽衍生物。可藉由用適合之稀鹼水溶液處理使游離鹼再生,該稀鹼水溶液諸如為稀NaOH水溶液、稀碳酸鉀水溶液、稀氨水溶液及稀碳酸氫鈉水溶液。舉例而言,在多種情況下,藉由將殺蟲劑(諸如2,4-D)轉化成其二甲胺鹽而使其為更可水溶的。
可將式I分子與溶劑一起調配成穩定錯合物,從而使該錯合物在移除未錯合溶劑後仍保持完整。此等錯合物經常被稱為「溶劑合物」。然而,與作為溶劑之水形成穩定的水合物為尤其所需。
式I分子可製成酯衍生物。此等酯衍生物接著可按與本文件中揭示之發明相同的施用方式來施用。
式I分子可製成各種結晶性多晶型物。多晶型性在農業化學之發展中為重要的,因為同一分子之不同結晶
性多晶型物或結構可具有截然不同的物理性質及生物效能。
式I分子可用不同的同位素製造。尤其重要的為具有代替1H之2H(亦稱為氘)之分子。
式I分子可用不同的放射性核素製造。尤其重要的為具有14C之分子。
立體異構體
式I分子可以一或多種立體異構體形式存在。因此,某些分子可以外消旋混合物形式製造。熟習此項技術者將瞭解,一種立體異構體可比其他立體異構體更具活性。個別立體異構體可藉由已知的選擇性合成程序獲得、使用經解析之起始物質藉由習知合成程序獲得或藉由習知解析程序來獲得。此文件中揭示之某些分子可以兩種或兩種以上異構體形式存在。各種異構體包括幾何異構體、非對映異構體及對映異構體。因此,此文件中揭示之分子包括幾何異構體、外消旋混合物、個別立體異構體及光學活性混合物。熟習此項技術者將瞭解,一種異構體可比其他異構體更具活性。本發明中揭示之結構出於清晰以僅一種幾何形式繪製,但意欲表示該分子之所有幾何形式。
組合
式I分子亦可與一或多種具有殺蟎、殺藻、殺卵、殺細菌、殺真菌、除草、殺昆蟲、殺軟體動物、殺線蟲、殺嚙齒類動物或殺病毒性質之化合物組合(諸如以組合混合物、或同時或依序施用形式)使用。此外,式I分子亦可與
作為拒食劑、驅鳥劑、化學絕育劑、除草劑安全劑、誘蟲劑、驅蟲劑、驅哺乳動物劑、交配干擾劑、植物活化劑、植物生長調節劑或增效劑之化合物組合(諸如以組合混合物、或同時或依序施用形式)使用。可與式I分子一起使用之上述群組中之該等化合物之實例為:溴化(3-乙氧基丙基)汞、1,2-二氯丙烷、1,3-二氯丙烯、1-甲基環丙烯、1-萘酚、2-(辛基硫基)乙醇、2,3,5-三-碘苯甲酸、2,3,6-TBA、2,3,6-TBA-二甲基銨、2,3,6-TBA-鋰、2,3,6-TBA-鉀、2,3,6-TBA-鈉、2,4,5-T、2,4,5-T-2-丁氧基丙基、2,4,5-T-2-乙基己基、2,4,5-T-3-丁氧基丙基、2,4,5-TB、2,4,5-T-丁氧基甲基、2,4,5-T-丁氧基乙基、2,4,5-T-丁基、2,4,5-T-異丁基、2,4,5-T-異辛基、2,4,5-T-異丙基、2,4,5-T-甲基、2,4,5-T-戊基、2,4,5-T-鈉、2,4,5-T-三乙基銨、2,4,5-T-三乙醇胺、2,4-D、2,4-D-2-丁氧基丙基、2,4-D-2-乙基己基、2,4-D-3-丁氧基丙基、2,4-D-銨、2,4-DB、2,4-DB-丁基、2,4-DB-二甲基銨、2,4-DB-異辛基、2,4-DB-鉀、2,4-DB-鈉、2,4-D-丁氧基乙基、2,4-D-丁基、2,4-D-二乙基銨、2,4-D-二甲基銨、2,4-D-二乙醇胺、2,4-D-十二烷基銨、2,4-DEB、2,4-DEP、2,4-D-乙基、2,4-D-庚基銨、2,4-D-異丁基、2,4-D-異辛基、2,4-D-異丙基、2,4-D-異丙基銨、2,4-D-鋰、2,4-D-甲基庚基、2,4-D-甲基、2,4-D-辛基、2,4-D-戊基、2,4-D-鉀、2,4-D-丙基、2,4-D-鈉、2,4-D-四氫呋喃基、2,4-D-四癸基銨、2,4-D-三乙基銨、2,4-D-參(2-羥基丙基)銨、2,4-D-三乙醇胺、2iP、氯化2-甲氧基乙基汞、2-苯基苯酚、3,4-DA、
3,4-DB、3,4-DP、4-胺基吡啶、4-CPA、4-CPA-鉀、4-CPA-鈉、4-CPB、4-CPP、4-羥基苯乙醇、8-羥基喹啉硫酸鹽、8-苯基汞基氧基喹啉、阿維菌素(abamectin)、脫落酸、ACC、歐殺松(acephate)、亞醌蟎(acequinocyl)、亞滅培(acetamiprid)、家蠅磷(acethion)、乙草胺(acetochlor)、乙酯磷(acetophos)、乙醯蟲腈(acetoprole)、阿拉酸式苯(acibenzolar)、阿拉酸式苯-S-甲基、三氟羧草醚、三氟羧草醚-甲基、三氟羧草醚-鈉、苯草醚(aclonifen)、內醯吖庚胺(acrep)、阿納寧(acrinathrin)、丙烯醛(acrolein)、丙烯腈(acrylonitrile)、八九十混酸(acypetacs)、八九十混酸-銅、八九十混酸-鋅、拉草(alachlor)、棉鈴威(alanycarb)、阿苯達唑(albendazole)、得滅克(aldicarb)、烯丙菊酯(aldimorph)、碸滅威(aldoxycarb)、艾氏劑(aldrin)、亞列寧(allethrin)、蒜素(allicin)、草毒死(allidochlor)、阿洛胺菌素(allosamidin)、亞汰草(alloxydim)、亞汰草-鈉、烯丙醇、除害威(allyxycarb)、五氯戊酮酸(alorac)、α-氯氰菊酯、α-安殺番(alpha-endosulfan)、辛唑嘧菌胺(ametoctradin)、特津酮(ametridione)、草殺凈(ametryn)、特草嗪酮(amibuzin)、胺唑草酮(amicarbazone)、拌種靈(amicarthiazol)、賽果(amidithion)、磺胺蟎酯(amidoflumet)、磺胺磺隆(amidosulfuron)、滅害威(aminocarb)、環丙嘧啶酸(aminocyclopyrachlor)、環丙嘧啶酸-甲基、環丙嘧啶酸-鉀、氯胺基吡啶酸(aminopyralid)、氯胺基吡啶酸-鉀、氯胺基吡啶酸-參(2-羥基丙基)銨、甲基胺草磷(amiprofos-methyl)、
胺草磷(amiprophos)、安美速(amisulbrom)、胺吸磷(amiton)、乙二酸胺吸磷(amiton oxalate)、三亞蟎(amitraz)、殺草強(amitrole)、胺磺酸銨(ammonium sulfamate)、α-萘乙酸銨、代森銨(amobam)、氨丙膦酸(ampropylfos)、新菸鹼(anabasine)、嘧啶醇(ancymidol)、敵菌靈(anilazine)、莎稗磷(anilofos)、疏草隆(anisuron)、蒽醌、安妥(antu)、唑磷嗪(apholate)、殺蟎特(aramite)、三氧化二砷、福美砷(asomate)、阿司匹靈(aspirin)、亞速爛(asulam)、亞速爛-鉀、亞速爛-鈉、艾噻達松(athidathion)、莠去通(atraton)、草脫凈(atrazine)、金色製黴素(aureofungin)、四烯雌酮(aviglycine)、四烯雌酮鹽酸鹽、阿紮康唑(azaconazole)、印楝素(azadirachtin)、草芬定(azafenidin)、唑啶磷(azamethiphos)、四唑磺隆(azimsulfuron)、益棉磷(azinphos-ethyl)、保棉磷(azinphos-methyl)、疊氮津(aziprotryne)、氧化福美雙(azithiram)、偶氮苯(azobenzene)、亞環錫(azocyclotin)、偶氮磷(azothoate)、亞托敏(azoxystrobin)、菊乙胺酯(bachmedesh)、燕麥靈(barban)、六氟矽酸鋇、多硫化鋇、熏蟲菊(barthrin)、BCPC、氟丁醯草胺(beflubutamid)、本達樂(benalaxyl)、本達樂-M、草除靈(benazolin)、草除靈-二甲基銨、草除靈-乙基、草除靈-鉀、苯卡巴松(bencarbazone)、苯氯噻(benclothiaz)、免敵克(bendiocarb)、倍尼芬(benfluralin)、免扶克(benfuracarb)、呋草磺(benfuresate)、麥鏽靈(benodanil)、免賴得(benomyl)、解草酮(benoxacor)、苯噁磷(benoxafos)、
醌肟腙(benquinox)、苄嘧磺隆(bensulfuron)、苄嘧磺隆-甲基、地散磷(bensulide)、免速達(bensultap)、丙唑草隆(bentaluron)、本達隆(bentazone)、本達隆-鈉、苯噻菌胺(benthiavalicarb)、苯噻菌胺-異丙基、苯噻硫氰(benthiazole)、草噁嗪(bentranil)、胺酸殺(benzadox)、胺酸殺-銨、苯紮氯銨(benzalkonium chloride)、苄烯酸(benzamacril)、苄烯酸異丁酯(benzamacril-isobutyl)、苯雜嗎(benzamorf)、雙苯嘧草酮(benzfendizone)、苄草胺(benzipram)、苯并雙環酮(benzobicyclon)、吡草酮(benzofenap)、氟磺胺草(benzofluor)、苯基異羥肟酸(benzohydroxamic acid)、西脫蟎(benzoximate)、新燕靈(benzoylprop)、新燕靈-乙基、噻草隆(benzthiazuron)、苯甲酸苯甲酯、苯甲基腺嘌呤(benzyladenine)、黃連素(berberine)、氯化黃連素(berberine chloride)、β-氟氯氰菊酯(beta-cyfluthrin)、β-氯氰菊酯(beta-cypermethrin)、苯噻噁嗪(bethoxazin)、雙環比隆(bicyclopyrone)、必芬蟎(bifenazate)、必芬諾(bifenox)、畢芬寧(bifenthrin)、吡氟菌酯(bifujunzhi)、畢拉草(bilanafos)、畢拉草-鈉、百蟎克(binapacryl)、病氰硝(bingqingxiao)、反式丙烯除蟲菊(bioallethrin)、生物乙酸次甲酯(bioethanomethrin)、生物氯菊酯(biopermethrin)、生物苄呋菊酯(bioresmethrin)、聯苯(biphenyl)、吡殺茲(bisazir)、噻枯唑(bismerthiazol)、雙草醚(bispyribac)、雙草醚-鈉、雙三氟蟲脲(bistrifluron)、聯苯三唑醇(bitertanol)、硫雙二氯酚(bithionol)、雙昔芬
(bixafen)、保米黴素(blasticidin-S)、硼砂(borax)、波爾多(Bordeaux mixture)、硼酸、白克列(boscalid)、芸苔素內酯(brassinolide)、芸苔素內酯-乙基、小蠹集合信息素(brevicomin)、溴鼠隆(brodifacoum)、溴滅菊酯(brofenvalerate)、溴氟菊酯(brofluthrinate)、克草(bromacil)、克草-鋰、克草-鈉、溴敵隆(bromadiolone)、溴鼠胺(bromethalin)、溴苄呋菊酯(bromethrin)、溴苯烯磷(bromfenvinfos)、溴乙醯胺(bromoacetamide)、糠草腈(bromobonil)、溴丁醯草胺(bromobutide)、溴烯殺(bromocyclen)、溴-DDT、殺草全(bromofenoxim)、溴硫磷(bromophos)、溴硫磷-乙基、溴蟎酯(bromopropylate)、溴菌腈(bromothalonil)、溴苯腈(bromoxynil)、丁酸溴苯腈(bromoxynil butyrate)、庚酸溴苯腈(bromoxynil heptanoate)、辛酸溴苯腈(bromoxynil octanoate)、溴苯腈-鉀、殺莠敏(brompyrazon)、溴克座(bromuconazole)、溴硝醇(bronopol)、增效特(bucarpolate)、合殺威(bufencarb)、佈敏納弗(buminafos)、佈瑞莫(bupirimate)、佈芬凈(buprofezin)、伯更狄混合液(Burgundy mixture)、白消安(busulfan)、畜蟲威(butacarb)、丁基拉草(butachlor)、氟丙嘧草酯(butafenacil)、抑草膦(butamifos)、特嘧硫磷(butathiofos)、丁烯草胺(butenachlor)、苄烯菊酯(butethrin)、特咪唑草(buthidazole)、丁硫啶(buthiobate)、丁噻隆(buthiuron)、佈嘉信(butocarboxim)、丁酯磷(butonate)、避蚊酮(butopyronoxyl)、氧丁叉威(butoxycarboxim)、比達寧
(butralin)、丁苯草酮(butroxydim)、炔草隆(buturon)、丁胺(butylamine)、拔敵草(butylate)、二甲胂酸(cacodylic acid)、硫線磷(cadusafos)、苯酮唑(cafenstrole)、砷酸鈣、氯酸鈣、氰氨化鈣(calcium cyanamide)、多硫化鈣(calcium polysulfide)、鈣殺畏(calvinphos)、克草胺酯(cambendichlor)、毒殺芬(camphechlor)、樟腦(camphor)、四氯丹(captafol)、蓋普丹(captan)、嗎菌威(carbamorph)、氯滅殺威(carbanolate)、加保利(carbaryl)、卡巴草靈(carbasulam)、貝芬替(carbendazim)、苯磺酸貝芬替(carbendazim benzenesulfonate)、亞硫酸貝芬替(carbendazim sulfite)、長殺草(carbetamide)、加保扶(carbofuran)、二硫化碳(carbon disulfide)、四氯化碳(carbon tetrachloride)、三硫磷(carbophenothion)、丁基加保扶(carbosulfan)、特噁唑威(carboxazole)、環二混劑(carboxide)、萎鏽靈(carboxin)、氟酮唑草(carfentrazone)、氟酮唑草-乙基(carfentrazone-ethyl)、加普胺(carpropamid)、培丹(cartap)、鹽酸培丹(cartap hydrochloride)、香芹酚(carvacrol)、香芹酮(carvone)、CDEA、滅胞素(cellocidin)、CEPC、西拉洛(ceralure)、切欣特混合液(Cheshunt mixture)、滅蟎猛(chinomethionat)、殼聚糖(chitosan)、滅瘟唑(chlobenthiazone)、甲氧基護穀(chlomethoxyfen)、氯醛糖(chloralose)、克爛本(chloramben)、克爛本-銨(chloramben-ammonium)、克爛本-二乙醇胺(chloramben-diolamine)、克爛本-甲基
(chloramben-methyl)、克爛本-甲基銨(chloramben-methylammonium)、克爛本-鈉(chloramben-sodium)、氯胺磷(chloramine phosphorus)、氯黴素(chloramphenicol)、雙胺靈(chloraniformethan)、氯醌(chloranil)、地快樂(chloranocryl)、剋安勃(chlorantraniliprole)、炔禾靈(chlorazifop)、炔禾靈-炔丙基(chlorazifop-propargyl)、可樂津(chlorazine)、氯殺蟎(chlorbenside)、滅幼脲(chlorbenzuron)、冰片丹(chlorbicyclen)、滅落寧(chlorbromuron)、氯炔靈(chlorbufam)、氯丹(chlordane)、開蓬(chlordecone)、殺蟲脒(chlordimeform)、殺蟲脒鹽酸鹽(chlordimeform hydrochloride)、(chlorempenthrin)、壤土氯磷(chlorethoxyfos)、乙氧苯隆(chloreturon)、伐草克(chlorfenac)、伐草克-銨(chlorfenac-ammonium)、伐草克-鈉(chlorfenac-sodium)、克凡派(chlorfenapyr)、苯咪唑菌(chlorfenazole)、殺蟎醇(chlorfenethol)、燕麥酯(chlorfenprop)、殺蟎酯(chlorfenson)、敵蟎丹(chlorfensulphide)、氯芬松(chlorfenvinphos)、克福隆(chlorfluazuron)、氟嘧殺(chlorflurazole)、氯芴酸(chlorfluren)、氯芴酸-甲基(chlorfluren-methyl)、氯甲丹(chlorflurenol)、氯甲丹-甲基(chlorflurenol-methyl)、氯草敏(chloridazon)、氯嘧磺隆(chlorimuron)、氯嘧磺隆-乙基(chlorimuron-ethyl)、氯甲磷(chlormephos)、矮壯素陽離子(chlormequat)、矮壯素(chlormequat chloride)、氯乙靈
(chlornidine)、草枯醚(chlornitrofen)、乙酯殺蟎醇(chlorobenzilate)、氯二硝基萘(chlorodinitronaphthalenes)、氯仿、伊托明(chloromebuform)、螟鈴畏(chloromethiuron)、二氯甲氧苯(chloroneb)、氯鼠酮(chlorophacinone)、氯鼠酮-鈉(chlorophacinone-sodium)、氯化苦(chloropicrin)、三氯丙酸(chloropon)、丙酯殺蟎醇(chloropropylate)、四氯異苯腈(chlorothalonil)、綠麥隆(chlorotoluron)、枯草隆(chloroxuron)、羥敵草腈(chloroxynil)、矮形磷(chlorphonium)、氯化磷(chlorphonium chloride)、氯腈肟磷(chlorphoxim)、氯吡唑磷(chlorprazophos)、草敗死(chlorprocarb)、氯苯胺靈(chlorpropham)、陶斯松(chlorpyrifos)、陶斯松-甲基(chlorpyrifos-methyl)、四氯喹噁啉(chlorquinox)、綠磺隆(chlorsulfuron)、敵草索(chlorthal)、敵草索-二甲基(chlorthal-dimethyl)、敵草索-單甲基(chlorthal-monomethyl)、草克樂(chlorthiamid)、氯甲硫磷(chlorthiophos)、克氯得(chlozolinate)、氯化膽鹼、可芬諾(chromafenozide)、瓜菊酯I(cinerin I)、瓜菊酯II(cinerin II)、瓜菊酯類(cinerins)、吲哚酮草酯(cinidon-ethyl)、環庚草醚(cinmethylin)、西速隆(cinosulfuron)、苯氰丁醯胺(ciobutide)、咯草隆(cisanilide)、順式苄呋菊酯(cismethrin)、克草同(clethodim)、氯咪巴唑(climbazole)、一氯吡啶酯(cliodinate)、炔草酯(clodinafop)、炔草酯-炔丙基(clodinafop-propargyl)、除線威(cloethocarb)、苯噠嗪鉀(clofencet)、苯噠嗪鉀-鉀(clofencet-potassium)、克芬蟎
(clofentezine)、氯貝酸(clofibric acid)、氯伏草(clofop)、氯伏草-異丁基(clofop-isobutyl)、可滅蹤(clomazone)、稗草胺(clomeprop)、調果酸(cloprop)、氯丙氧定(cloproxydim)、畢克草(clopyralid)、畢克草-甲基(clopyralid-methyl)、畢克草-醇胺(clopyralid-olamine)、畢克草-鉀(clopyralid-potassium)、畢克草-參(2-羥丙基)銨、解毒喹(cloquintocet)、解毒喹-甲基(cloquintocet-mexyl)、氯酯磺草胺(cloransulam)、氯酯磺草胺-甲基(cloransulam-methyl)、氯生太爾(closantel)、可尼丁(clothianidin)、克黴唑(clotrimazole)、座果酸(cloxyfonac)、座果酸-鈉(cloxyfonac-sodium)、CMA、十二碳二烯醇(codlelure)、噻唑硫磷(colophonate)、乙酸銅、乙醯亞砷酸銅、砷酸銅、鹼式碳酸銅、氫氧化銅、環烷酸銅、油酸銅、氯氧化銅、矽酸銅、硫酸銅、鉻酸鋅銅、氯殺鼠靈(coumachlor)、克滅鼠(coumafuryl)、蠅毒磷(coumaphos)、殺鼠迷(coumatetralyl)、畜蟲磷(coumithoate)、丁香菌酯(coumoxystrobin)、CPMC、CPMF、CPPC、噠草醚(credazine)、甲酚(cresol)、甲基鼠滅定(crimidine)、克羅米通(crotamiton)、丁烯磷(crotoxyphos)、克蘆磷酯(crufomate)、冰晶石(cryolite)、誘蠅酮(cue-lure)、硫雜靈(cufraneb)、苄草隆(cumyluron)、殺菌威(cuprobam)、氧化亞銅、莪術醇(curcumenol)、氰胺、氰草淨(cyanatryn)、氰乃淨(cyanazine)、苯腈磷(cyanofenphos)、氰乃松(cyanophos)、果蟲磷(cyanthoate)、氰蟲醯胺(cyantraniliprole)、賽座滅(cyazofamid)、賽百摧
(cybutryne)、環菌胺(cyclafuramid)、環丙醯胺酸(cyclanilide)、環蟲菊(cyclethrin)、環草特(cycloate)、環己醯亞胺(cycloheximide)、環蟎酯(cycloprate)、乙氰菊酯(cycloprothrin)、環磺隆(cyclosulfamuron)、環氧蟲啶(cycloxaprid)、環殺草(cycloxydim)、環莠隆(cycluron)、塞諾吡芬(cyenopyrafen)、賽芬胺(cyflufenamid)、丁氟蟎酯(cyflumetofen)、賽扶寧(cyfluthrin)、氰氟草酯(cyhalofop)、氰氟草酯-丁基(cyhalofop-butyl)、賽洛寧(cyhalothrin)、錫蟎丹(cyhexatin)、蟎蜱胺(cymiazole)、蟎蜱胺鹽酸鹽(cymiazole hydrochloride)、克絕(cymoxanil)、解草胺腈(cyometrinil)、氰菌靈(cypendazole)、賽滅寧(cypermethrin)、牧草快(cyperquat)、牧草快氯化物(cyperquat chloride)、賽酚寧(cyphenothrin)、環丙津(cyprazine)、三環噻草胺(cyprazole)、環克座(cyproconazole)、賽普洛(cyprodinil)、酯菌胺(cyprofuram)、環草胺(cypromid)、環丙磺醯胺(cyprosulfamide)、賽滅淨(cyromazine)、賽滅磷(cythioate)、香草隆(daimuron)、得拉本(dalapon)、得拉本-鈣(dalapon-calcium)、得拉本-鎂(dalapon-magnesium)、得拉本-鈉(dalapon-sodium)、丁醯肼(daminozide)、噠幼酮(dayoutong)、邁隆(dazomet)、邁隆-鈉(dazomet-sodium)、DBCP、d-樟腦(d-camphor)、DCIP、DCPTA、DDT、咪菌威(debacarb)、癸磷錫(decafentin)、一甲呋喃丹(decarbofuran)、脫氫乙酸(dehydroacetic acid)、異丁草胺(delachlor)、第滅寧(deltamethrin)、田樂磷(demephion)、田
樂磷-O(demephion-O)、田樂磷-S(demephion-S)、內吸磷(demeton)、甲基內吸磷(demeton-methyl)、內吸磷-O(demeton-O)、內吸磷-O-甲基(demeton-O-methyl)、內吸磷-S(demeton-S)、內吸磷-S-甲基(demeton-S-methyl)、內吸磷-S-甲基硫(demeton-S-methylsulphon)、甜菜安(desmedipham)、敵草淨(desmetryn)、d-反式氯炔丙菊酯(d-fanshiluquebingjuzhi)、汰芬隆(diafenthiuron)、氯亞磷(dialifos)、燕麥敵(di-allate)、除線特(diamidafos)、矽藻土(diatomaceous earth)、大利松(diazinon)、鄰苯二甲酸二丁酯、丁二酸二丁酯、汰克草(dicamba)、汰克草-二甘醇胺(dicamba-diglycolamine)、汰克草-二甲銨(dicamba-dimethylammonium)、汰克草-二乙醇胺(dicamba-diolamine)、汰克草-異丙銨(dicamba-isopropylammonium)、汰克草-甲基(dicamba-methyl)、汰克草-醇胺(dicamba-olamine)、汰克草-鉀(dicamba-potassium)、汰克草-鈉(dicamba-sodium)、汰克草-三乙醇胺(dicamba-trolamine)、異氯磷(dicapthon)、二氯苯腈(dichlobenil)、除線磷(dichlofenthion)、益發靈(dichlofluanid)、二氯萘醌(dichlone)、氯雙脲(dichloralurea)、滅幼脲(dichlorbenzuron)、二氯甲丹(dichlorflurenol)、二氯甲丹-甲基(dichlorflurenol-methyl)、苄胺靈(dichlormate)、二氯丙烯胺(dichlormid)、雙氯酚(dichlorophen)、2,4-滴丙酸(dichlorprop)、2,4-滴丙酸-2-乙基己基(dichlorprop-2-ethylhexyl)、2,4-滴丙酸-丁氧基乙酯
(dichlorprop-butotyl)、2,4-滴丙酸-二甲銨(dichlorprop-dimethylammonium)、2,4-滴丙酸-乙銨(dichlorprop-ethylammonium)、2,4-滴丙酸-異辛酯(dichlorprop-isoctyl)、2,4-滴丙酸-甲基(dichlorprop-methyl)、高2,4-滴丙酸(dichlorprop-P)、高2,4-滴丙酸-2-乙基己基(dichlorprop-P-2-ethylhexyl)、高2,4-滴丙酸-二甲銨(dichlorprop-P-dimethylammonium)、2,4-滴丙酸-鉀(dichlorprop-potassium)、2,4-滴丙酸-鈉(dichlorprop-sodium)、二氯松(dichlorvos)、菌核利(dichlozoline)、苄氯三唑醇(diclobutrazol)、雙氯氰菌胺(diclocymet)、禾草靈(diclofop)、禾草靈-甲基(diclofop-methyl)、達滅淨(diclomezine)、達滅淨-鈉(diclomezine-sodium)、大克爛(dicloran)、雙氯磺草胺(diclosulam)、大克蟎(dicofol)、雙香豆素(dicoumarol)、聯甲苯(dicresyl)、雙特松(dicrotophos)、環蟲腈(dicyclanil)、二環隆(dicyclonon)、狄氏劑(dieldrin)、除蟎靈(dienochlor)、迭森刈(diethamquat)、迭森刈二氯化物(diethamquat dichloride)、乙醯甲草胺(diethatyl)、乙醯甲草胺-乙基(diethatyl-ethyl)、乙黴威(diethofencarb)、迪艾索諾(dietholate)、焦碳酸二乙酯(diethyl pyrocarbonate)、二乙甲苯醯胺(diethyltoluamide)、鼠得克(difenacoum)、待克利(difenoconazole)、戊味禾草靈(difenopenten)、戊味禾草靈-乙基(difenopenten-ethyl)、枯莠隆(difenoxuron)、野燕枯(difenzoquat)、野燕枯甲硫酸鹽(difenzoquat metilsulfate)、
噻鼠靈(difethialone)、氟蟎嗪(diflovidazin)、二福隆(diflubenzuron)、吡氟醯草胺(diflufenican)、氟吡草腙(diflufenzopyr)、氟吡草腙-鈉(diflufenzopyr-sodium)、二氟林(diflumetorim)、敵草克(dikegulac)、敵草克-鈉(dikegulac-sodium)、滴露(dilor)、滴馬提夫(dimatif)、四氟甲醚菊酯(dimefluthrin)、甲氟磷(dimefox)、噁唑隆(dimefuron)、哌草丹(dimepiperate)、菌核淨(dimetachlone)、地麥威(dimetan)、混滅威(dimethacarb)、二甲草胺(dimethachlor)、戊草津(dimethametryn)、汰草滅(dimethenamid)、汰草滅-P(dimethenamid-P)、噻節因(dimethipin)、二甲嘧酚(dimethirimol)、大滅松(dimethoate)、達滅芬(dimethomorph)、苄菊酯(dimethrin)、卡百酸二甲酯(dimethyl carbate)、鄰苯二甲酸二甲酯、二甲基毒蟲畏(dimethylvinphos)、敵蠅威(dimetilan)、草滅散(dimexano)、敵米達松(dimidazon)、醚菌胺(dimoxystrobin)、消蟎酚(dinex)、消蟎酚-迪克辛(dinex-diclexine)、啶菌噁唑(dingjunezuo)、達克利(diniconazole)、達克利-M(diniconazole-M)、撻乃安(dinitramine)、消蟎通(dinobuton)、白粉克(dinocap)、白粉克-4(dinocap-4)、白粉克-6(dinocap-6)、敵菌死(dinocton)、消草酯(dinofenate)、硝戊酯(dinopenton)、硝丙酚(dinoprop)、戊硝酚(dinosam)、達諾殺(dinoseb)、達諾殺乙酸酯(dinoseb acetate)、達諾殺-銨(dinoseb-ammonium)、達諾殺-二乙醇胺(dinoseb-diolamine)、達諾殺-鈉(dinoseb-sodium)、達諾殺-
三乙醇胺(dinoseb-trolamine)、硝辛酯(dinosulfon)、達特南(dinotefuran)、特樂酚(dinoterb)、特樂酚乙酸酯(dinoterb acetate)、硝丁酯(dinoterbon)、二苯丙醚(diofenolan)、蔬果磷(dioxabenzofos)、二氧威(dioxacarb)、敵殺磷(dioxathion)、二苯茚酮(diphacinone)、二苯茚酮-鈉(diphacinone-sodium)、大芬滅(diphenamid)、二苯碸、二苯胺、胺樂靈(dipropalin)、異丙淨(dipropetryn)、雙硫氧吡啶(dipyrithione)、敵草快(diquat)、敵草快二溴化物(diquat dibromide)、環氧十九烷(disparlure)、賽松(disul)、雙硫侖(disulfiram)、二硫松(disulfoton)、賽松-鈉(disul-sodium)、滅菌磷(ditalimfos)、腈硫醌(dithianon)、苯噻乙雙硫磷(dithicrofos)、二硫醚、汰硫草(dithiopyr)、達有龍(diuron)、d-檸檬烯(d-limonene)、DMPA、DNOC、DNOC-銨、DNOC-鉀、DNOC-鈉、嗎菌靈(dodemorph)、嗎菌靈乙酸鹽(dodemorph acetate)、嗎菌靈苯甲酸鹽(dodemorph benzoate)、多地辛(dodicin)、多地辛鹽酸鹽(dodicin hydrochloride)、多地辛-鈉(dodicin-sodium)、多寧(dodine)、多芬那比(dofenapyn)、多明尼卡路(dominicalure)、多拉菌素(doramectin)、敵菌酮(drazoxolon)、DSMA、毒氟磷(dufulin)、EBEP、EBP、蛻皮甾酮(ecdysterone)、護粒松(edifenphos)、甘草津(eglinazine)、甘草津-乙基(eglinazine-ethyl)、埃瑪菌素(emamectin)、埃瑪菌素苯甲酸鹽(emamectin benzoate)、EMPC、烯炔菊酯(empenthrin)、安殺番(endosulfan)、草哆嗦(endothal)、草哆嗦-二銨
(endothal-diammonium)、草哆嗦-二鉀(endothal-dipotassium)、草哆嗦-二鈉(endothal-disodium)、內毒磷(endothion)、異狄氏劑(endrin)、烯肟菌酯(enestroburin)、EPN、丙醯芸苔素內酯(epocholeone)、保幼醚(epofenonane)、依普座(epoxiconazole)、依普菌素(eprinomectin)、三唑磺(epronaz)、EPTC、抑草蓬(erbon)、鈣化醇(ergocalciferol)、二氯醯草胺(erlujixiancaoan)、生物烯丙菊酯(esdépalléthrine)、高氰戊菊酯(esfenvalerate)、戊草丹(esprocarb)、乙烯矽(etacelasil)、乙環唑(etaconazole)、丙硫磷(etaphos)、伊特姆(etem)、噻唑菌胺(ethaboxam)、克草胺(ethachlor)、丁氟消草(ethalfluralin)、胺苯磺隆(ethametsulfuron)、胺苯磺隆-甲基(ethametsulfuron-methyl)、殺草胺(ethaprochlor)、乙烯利(ethephon)、磺噻隆(ethidimuron)、乙硫苯威(ethiofencarb)、抑草威(ethiolate)、愛殺松(ethion)、乙嗪草酮(ethiozin)、乙蟲清(ethiprole)、依瑞莫(ethirimol)、益硫磷-甲基(ethoate-methyl)、益覆滅(ethofumesate)、乙基己二醇(ethohexadiol)、普伏松(ethoprophos)、氯氟草醚(ethoxyfen)、氯氟草醚-乙基(ethoxyfen-ethyl)、乙氧喹啉(ethoxyquin)、亞速隆(ethoxysulfuron)、吲唑酯(ethychlozate)、甲酸乙酯(ethyl formate)、α-萘乙酸乙酯(ethyl α-naphthaleneacetate)、乙基1-DDD、乙烯、二溴乙烷(ethylene dibromide)、二氯乙烷(ethylene dichloride)、環氧乙烷(ethylene oxide)、乙蒜素(ethylicin)、乙基汞2,3-二羥基丙基
硫醇、乙基汞乙酸鹽、乙基汞溴化物、乙基汞氯化物、乙基汞磷酸鹽(ethylmercury phosphate)、硝草酚(etinofen)、艾尼丙密(etnipromid)、乙氧苯草胺(etobenzanid)、依芬寧(etofenprox)、依殺蟎(etoxazole)、依得利(etridiazole)、乙氧嘧啶磷(etrimfos)、丁香酚(eugenol)、EXD、凡殺同(famoxadone)、伐滅磷(famphur)、咪唑菌酮(fenamidone)、敵磺鈉(fenaminosulf)、芬滅松(fenamiphos)、咪菌腈(fenapanil)、芬瑞莫(fenarimol)、芬磺草靈(fenasulam)、抗蟎唑(fenazaflor)、芬殺蟎(fenazaquin)、芬克座(fenbuconazole)、苯丁錫(fenbutatin oxide)、解草唑(fenchlorazole)、解草唑-乙基(fenchlorazole-ethyl)、皮蠅磷(fenchlorphos)、解草啶(fenclorim)、雙乙威(fenethacarb)、芬氟司林(fenfluthrin)、甲呋醯胺(fenfuram)、環醯菌胺(fenhexamid)、種衣酯(fenitropan)、撲滅松(fenitrothion)、酚菌酮(fenjuntong)、丁基滅必蝨(fenobucarb)、2,4,5-涕丙酸(fenoprop)、2,4,5-涕丙酸-3-丁氧基丙基(fenoprop-3-butoxypropyl)、2,4,5-涕丙酸-丁氧基甲基(fenoprop-butometyl)、2,4,5-涕丙酸-丁氧基乙酯(fenoprop-butotyl)、2,4,5-涕丙酸-丁基(fenoprop-butyl)、2,4,5-涕丙酸-異辛基(fenoprop-isoctyl)、2,4,5-涕丙酸-甲基(fenoprop-methyl)、2,4,5-涕丙酸-鉀(fenoprop-potassium)、苯硫威(fenothiocarb)、嘧醯蟲胺(fenoxacrim)、芬諾尼(fenoxanil)、噁唑禾草靈(fenoxaprop)、噁唑禾草靈-乙基(fenoxaprop-ethyl)、噁唑禾草靈-P(fenoxaprop-P)、噁唑禾
草靈-P-乙基(fenoxaprop-P-ethyl)、酚奧薩碸(fenoxasulfone)、苯氧威(fenoxycarb)、拌種咯(fenpiclonil)、吡氯氰菊酯(fenpirithrin)、芬普寧(fenpropathrin)、苯鏽啶(fenpropidin)、芬普福(fenpropimorph)、胺苯吡菌酮(fenpyrazamine)、芬普蟎(fenpyroximate)、殺雄嗪(fenridazon)、殺雄嗪-鉀(fenridazon-potassium)、殺雄嗪-丙基(fenridazon-propyl)、除蟎酯(fenson)、繁福松(fensulfothion)、芬特拉科(fenteracol)、噻唑禾草靈(fenthiaprop)、噻唑禾草靈-乙基(fenthiaprop-ethyl)、芬殺松(fenthion)、芬殺松-乙基(fenthion-ethyl)、三苯錫(fentin)、三苯錫乙酸鹽(fentin acetate)、三苯錫氯化物(fentin chloride)、三苯錫氫氧化物(fentin hydroxide)、四唑醯草胺(fentrazamide)、芬氟胺(fentrifanil)、非草隆(fenuron)、非草隆TCA(fenuron TCA)、芬化利(fenvalerate)、富爾邦(ferbam)、富米綜(ferimzone)、硫酸亞鐵、芬普尼(fipronil)、麥草伏(flamprop)、麥草伏-異丙基(flamprop-isopropyl)、麥草伏-M(flamprop-M)、麥草伏-甲基(flamprop-methyl)、麥草伏-M-異丙基(flamprop-M-isopropyl)、麥草伏-M-甲基(flamprop-M-methyl)、伏速隆(flazasulfuron)、伏滅鼠(flocoumafen)、弗美托奎(flometoquin)、氟尼胺(flonicamid)、雙氟磺草胺(florasulam)、嘧蟎酯(fluacrypyrim)、伏寄普(fluazifop)、伏寄普-丁基(fluazifop-butyl)、伏寄普-甲基(fluazifop-methyl)、伏寄普-P(fluazifop-P)、伏寄普-P-丁基(fluazifop-P-butyl)、扶吉胺
(fluazinam)、異丙吡草酯(fluazolate)、氟佐隆(fluazuron)、福本胺(flubendiamide)、氟奔絕胺(flubenzimine)、氟酮磺隆(flucarbazone)、氟酮磺隆-鈉(flucarbazone-sodium)、氟吡磺隆(flucetosulfuron)、氟消草(fluchloralin)、氟氰戊菊酯(flucofuron)、氟環脲(flucycloxuron)、護賽寧(flucythrinate)、護汰寧(fludioxonil)、聯氟蟎(fluenetil)、氟噻蟲碸(fluensulfone)、氟噻草胺(flufenacet)、氟芬林(flufenerim)、氟芬尼康(flufenican)、氟芬隆(flufenoxuron)、三氟醚菊酯(flufenprox)、氟噠嗪草酯(flufenpyr)、氟噠嗪草酯-乙基(flufenpyr-ethyl)、丁蟲腈(flufiprole)、氟氯苯氰菊酯(flumethrin)、氟醯菌胺(flumetover)、氟節胺(flumetralin)、唑嘧磺草胺(flumetsulam)、氟默嗪(flumezin)、氟胺草酯(flumiclorac)、氟胺草酯-戊基(flumiclorac-pentyl)、丙炔氟草胺(flumioxazin)、炔草胺(flumipropyn)、氟嗎啉(flumorph)、可奪草(fluometuron)、氟比來(fluopicolide)、氟吡菌醯胺(fluopyram)、氟殺蟎(fluorbenside)、增糖胺(fluoridamid)、氟乙醯胺(fluoroacetamide)、消草醚(fluorodifen)、乙羧氟草醚(fluoroglycofen)、乙羧氟草醚-乙基(fluoroglycofen-ethyl)、氟醯亞胺(fluoroimide)、唑啶草(fluoromidine)、氟除草醚(fluoronitrofen)、氟速隆(fluothiuron)、三氟苯唑(fluotrimazole)、氟嘧菌酯(fluoxastrobin)、氟胺草唑(flupoxam)、氟丙鉑秀(flupropacil)、氟鼠啶(flupropadine)、氟丙酸(flupropanate)、氟丙酸-鈉(flupropanate-sodium)、弗
比南載夫隆(flupyradifurone)、氟啶嘧磺隆(flupyrsulfuron)、氟啶嘧磺隆-甲基(flupyrsulfuron-methyl)、氟啶嘧磺隆-甲基-鈉(flupyrsulfuron-methyl-sodium)、氟喹唑(fluquinconazole)、解草安(flurazole)、抑草丁(flurenol)、抑草丁-丁基(flurenol-butyl)、抑草丁-甲基(flurenol-methyl)、氟啶草酮(fluridone)、氟咯草酮(flurochloridone)、氯氟吡氧乙酸(fluroxypyr)、氯氟吡氧乙酸-丁氧基甲酯(fluroxypyr-butometyl)、氯氟吡氧乙酸-甲基庚酯(fluroxypyr-meptyl)、呋嘧醇(flurprimidol)、硫氟磺醯胺(flursulamid)、呋草酮(flurtamone)、護矽得(flusilazole)、氟硫滅(flusulfamide)、噠草氟(fluthiacet)、噠草氟-甲基(fluthiacet-methyl)、氟噻菌淨(flutianil)、福多寧(flutolanil)、護汰芬(flutriafol)、氟胺氰菊酯(fluvalinate)、氟唑菌醯胺(fluxapyroxad)、肟草安(fluxofenim)、福爾培(folpet)、氟磺胺草醚(fomesafen)、氟磺胺草醚-鈉(fomesafen-sodium)、地蟲磷(fonofos)、甲醯嘧磺隆(foramsulfuron)、氟吡脲(forchlorfenuron)、甲醛、複滅蟎(formetanate)、複滅蟎鹽酸鹽(formetanate hydrochloride)、安果(formothion)、藻蟎滅(formparanate)、藻蟎滅鹽酸鹽(formparanate hydrochloride)、調節膦(fosamine)、調節膦-銨(fosamine-ammonium)、三乙膦酸(fosetyl)、三乙膦酸-銨(fosetyl-aluminium)、丁苯硫磷(fosmethilan)、福司吡酯(fospirate)、福賽絕(fosthiazate)、丁硫環磷(fosthietan)、弗羅塔林(frontalin)、麥穗靈(fuberidazole)、氟草淨
(fucaojing)、氟草醚(fucaomi)、氟奈西草林(funaihecaoling)、呋苯硫脲(fuphenthiourea)、乙二醇縮糠醛(furalane)、呋霜靈(furalaxyl)、炔呋菊酯(furamethrin)、福拉比(furametpyr)、呋線威(furathiocarb)、二甲呋醯胺(furcarbanil)、呋菌唑(furconazole)、呋菌唑-順式(furconazole-cis)、糠醛菊酯(furethrin)、糠醛(furfural)、呋喃解草唑(furilazole)、伴種胺(furmecyclox)、呋甲硫菌靈(furophanate)、呋氧草醚(furyloxyfen)、γ-賽洛寧(gamma-cyhalothrin)、γ-HCH(gamma-HCH)、格蟎酯(genit)、赤黴酸(gibberellic acid)、赤黴素(gibberellins)、甘氟(gliftor)、固殺草(glufosinate)、固殺草-銨(glufosinate-ammonium)、固殺草-P(glufosinate-P)、固殺草-P-銨(glufosinate-P-ammonium)、固殺草-P-鈉(glufosinate-P-sodium)、果綠定(glyodin)、乙二肟(glyoxime)、嘉磷塞(glyphosate)、嘉磷塞-二銨(glyphosate-diammonium)、嘉磷塞-二甲銨(glyphosate-dimethylammonium)、嘉磷塞-異丙銨(glyphosate-isopropylammonium)、嘉磷塞-單銨(glyphosate-monoammonium)、嘉磷塞-鉀(glyphosate-potassium)、嘉磷塞-倍半鈉(glyphosate-sesquisodium)、嘉磷塞-三甲基硫鹽(glyphosate-trimesium)、草甘二膦(glyphosine)、誘蟲十六酯(gossyplure)、誘殺烯混劑(grandlure)、灰黃黴素(griseofulvin)、雙胍辛胺(guazatine)、雙胍辛胺乙酸鹽
(guazatine acetates)、丙烯酸喹啉酯(halacrinate)、合芬寧(halfenprox)、氯蟲醯肼(halofenozide)、鹵索芬(halosafen)、氯吡嘧磺隆(halosulfuron)、氯吡嘧磺隆-甲基(halosulfuron-methyl)、氟啶草(haloxydine)、吡氟氯禾靈(haloxyfop)、吡氟氯禾靈-乙氧基乙酯(haloxyfop-etotyl)、吡氟氯禾靈-甲基(haloxyfop-methyl)、精吡氟氯禾靈(haloxyfop-P)、精吡氟氯禾靈-乙氧基乙酯(haloxyfop-P-etotyl)、精吡氟氯禾靈-甲基(haloxyfop-P-methyl)、吡氟氯禾靈-鈉(haloxyfop-sodium)、HCH、六甲蜜胺(hemel)、海母帕(hempa)、HEOD、七氯(heptachlor)、庚烯磷(heptenophos)、增產肟(heptopargil)、速殺硫磷(heterophos)、六氯丙酮(hexachloroacetone)、六氯苯(hexachlorobenzene)、六氯丁二烯(hexachlorobutadiene)、六氯酚(hexachlorophene)、菲克利(hexaconazole)、六伏隆(hexaflumuron)、六氟砷(hexaflurate)、紅鈴誘烯(hexalure)、己醯胺(hexamide)、菲殺淨(hexazinone)、己基硫福思(hexylthiofos)、合賽多(hexythiazox)、HHDN、赫洛塞呋(holosulf)、磺硝肟(huancaiwo)、磺草靈(huangcaoling)、環菌唑(huanjunzuo)、伏蟻腙(hydramethylnon)、汞加芬(hydrargaphen)、熟石灰(hydrated lime)、氰化氫(hydrogen cyanide)、烯蟲乙酯(hydroprene)、殺紋寧(hymexazol)、亥喹卡(hyquincarb)、IAA、IBA、埃卡瑞丁(icaridin)、依滅列(imazalil)、依滅列硝酸鹽(imazalil nitrate)、依滅列硫酸鹽(imazalil sulfate)、咪草酸(imazamethabenz)、咪草酸-甲基
(imazamethabenz-methyl)、甲氧咪草酸(imazamox)、甲氧咪草酸-銨(imazamox-ammonium)、甲咪唑菸酸(imazapic)、甲咪唑菸酸-銨(imazapic-ammonium)、依滅草(imazapyr)、依滅草-異丙銨(imazapyr-isopropylammonium)、滅草喹(imazaquin)、滅草喹-銨(imazaquin-ammonium)、滅草喹-甲基(imazaquin-methyl)、滅草喹-鈉(imazaquin-sodium)、咪草菸(imazethapyr)、咪草菸-銨(imazethapyr-ammonium)、依速隆(imazosulfuron)、易胺座(imibenconazole)、咪克芬(imicyafos)、益達胺、氯噻啉(imidaclothiz)、克熱淨(iminoctadine)、克熱淨三乙酸鹽(iminoctadine triacetate)、克熱淨三苯磺酸(iminoctadine trialbesilate)、炔咪菊酯(imiprothrin)、依納素(inabenfide)、茚草酮(indanofan)、三嗪茚草胺(indaziflam)、因得克(indoxacarb)、枯瘟淨(inezin)、碘保諾(iodobonil)、碘卡佈(iodocarb)、碘甲烷(iodomethane)、碘磺隆(iodosulfuron)、碘磺隆-甲基(iodosulfuron-methyl)、碘磺隆-甲基-鈉(iodosulfuron-methyl-sodium)、碘芬磺隆(iofensulfuron)、碘芬磺隆-鈉(iofensulfuron-sodium)、碘苯腈(ioxynil)、碘苯腈辛酸鹽(ioxynil octanoate)、碘苯腈-鋰(ioxynil-lithium)、碘苯腈-鈉(ioxynil-sodium)、依哌嗪(ipazine)、種菌唑(ipconazole)、三唑苯胺(ipfencarbazone)、丙基喜樂松(iprobenfos)、依普同(iprodione)、纈黴威(iprovalicarb)、氯胺草啶鹼(iprymidam)、小蟲二醇烯(ipsdienol)、小蟲醇烯(ipsenol)、IPSP、依沙米多福(isamidofos)、依殺松
(isazofos)、碳氯靈(isobenzan)、丁脒醯胺(isocarbamid)、水胺硫磷(isocarbophos)、異草定(isocil)、異艾氏劑(isodrin)、亞芬松(isofenphos)、亞芬松-甲基(isofenphos-methyl)、異索威(isolan)、丁嗪草酮(isomethiozin)、異草完隆(isonoruron)、異丙靈(isopolinate)、滅必虱(isoprocarb)、異樂靈(isopropalin)、亞賜圃(isoprothiolane)、異丙隆(isoproturon)、異比贊(isopyrazam)、異皮莫(isopyrimol)、獲賜松(isothioate)、異噻菌胺(isotianil)、愛速隆(isouron)、異醯菌酮(isovaledione)、異噁草胺(isoxaben)、異噁氯妥(isoxachlortole)、雙苯噁唑酸(isoxadifen)、雙苯噁唑酸-乙基(isoxadifen-ethyl)、異噁唑草酮(isoxaflutole)、異噁草醚(isoxapyrifop)、加福松(isoxathion)、伊維菌素(ivermectin)、淨種磷(izopamfos)、茉莉油(japonilure)、喃烯菊酯(japothrins)、喃烯菊酯I(jasmolin I)、喃烯菊酯II(jasmolin II)、茉莉酸(jasmonic acid)、甲磺蒽腙(jiahuangchongzong)、甲基硝啉(jiajizengxiaolin)、甲香菊酯(jiaxiangjunzhi)、解草完(jiecaowan)、解草稀(jiecaoxi)、碘硫磷(jodfenphos)、保幼激素I(juvenile hormone I)、保幼激素II(juvenile hormone II)、保幼激素III(juvenile hormone III)、噻嗯菊酯(kadethrin)、卡草靈(karbutilate)、卡列他南(karetazan)、卡列他南-鉀(karetazan-potassium)、嘉賜黴素(kasugamycin)、嘉賜黴素鹽酸鹽(kasugamycin hydrochloride)、柯均林(kejunlin)、氯戊環(kelevan)、酮螺氧(ketospiradox)、酮螺氧-鉀(ketospiradox-potassium)、細胞分裂素(kinetin)、烯蟲
炔酯(kinoprene)、克收欣(kresoxim-methyl)、庫卡辛(kuicaoxi)、乳氟禾草靈(lactofen)、λ-賽洛寧(lambda-cyhalothrin)、拉提路(latilure)、砷酸鉛(lead arsenate)、環草定(lenacil)、雷匹美汀(lepimectin)、福賜松(leptophos)、林丹(lindane)、雷尼汀(lineatin)、理有龍(linuron)、丙嘧啶磷(lirimfos)、利露(litlure)、誘池蛾酯(looplure)、祿芬隆(lufenuron)、氯啶菌酯(lvdingjunzhi)、氯醯草膦(lvxiancaolin)、噻唑磷(lythidathion)、MAA、馬拉松(malathion)、順丁烯二醯肼(maleic hydrazide)、丁苄腈(malonoben)、麥芽糊精(maltodextrin)、MAMA、代森錳銅(mancopper)、鋅錳乃浦(mancozeb)、曼普胺(mandipropamid)、錳乃浦(maneb)、苦參鹼(matrine)、疊氮磷(mazidox)、MCPA、MCPA-2-乙基己基、MCPA-丁氧基乙酯、MCPA-丁基、MCPA-二甲銨、MCPA-二乙醇胺、MCPA-乙基、MCPA-異丁基、MCPA-異辛基、MCPA-異丙基、MCPA-甲基、MCPA-醇胺、MCPA-鉀、MCPA-鈉、MCPA-硫乙基、MCPA-三乙醇胺、MCPB、MCPB-乙基、MCPB-甲基、MCPB-鈉、滅鏽胺(mebenil)、滅加松(mecarbam)、苯并威(mecarbinzid)、甲基滅蚜磷(mecarphon)、甲氯丙酸(mecoprop)、甲氯丙酸-2-乙基己基(mecoprop-2-ethylhexyl)、甲氯丙酸-二甲銨(mecoprop-dimethylammonium)、甲氯丙酸-二醇胺(mecoprop-diolamine)、甲氯丙酸-乙二基(mecoprop-ethadyl)、甲氯丙酸-異辛基(mecoprop-isoctyl)、
甲氯丙酸-甲基(mecoprop-methyl)、甲氯丙酸-P(mecoprop-P)、甲氯丙酸-P-2-乙基己基(mecoprop-P-2-ethylhexyl)、甲氯丙酸-P-二甲銨(mecoprop-P-dimethylammonium)、甲氯丙酸-P-異丁基(mecoprop-P-isobutyl)、甲氯丙酸-鉀(mecoprop-potassium)、甲氯丙酸-P-鉀(mecoprop-P-potassium)、甲氯丙酸-鈉(mecoprop-sodium)、甲氯丙酸-三乙醇胺(mecoprop-trolamine)、殺蟎脒(medimeform)、地樂施(medinoterb)、地樂施乙酸鹽(medinoterb acetate)、誘殺酯(medlure)、滅芬草(mefenacet)、吡唑二酸(mefenpyr)、吡唑二酸-二乙基(mefenpyr-diethyl)、氟磺醯胺草(mefluidide)、氟磺醯胺草-二醇胺(mefluidide-diolamine)、氟磺醯胺草-鉀(mefluidide-potassium)、十四碳二烯酸(megatomoic acid)、滅蚜松(menazon)、滅派林(mepanipyrim)、氯氟醚菊酯(meperfluthrin)、甲苯諾(mephenate)、二噻磷(mephosfolan)、甲哌啶(mepiquat)、甲哌啶氯化物(mepiquat chloride)、甲哌啶五硼酸鹽(mepiquat pentaborate)、滅普寧(mepronil)、敵蟎普(meptyldinocap)、氯化汞(mercuric chloride)、氧化汞(mercuric oxide)、氯化亞汞(mercurous chloride)、脫葉亞磷(merphos)、甲普拉嗪(mesoprazine)、甲基二磺隆(mesosulfuron)、甲基二磺隆-甲基(mesosulfuron-methyl)、甲基磺草酮(mesotrione)、甲硫芬(mesulfen)、倍硫磷亞碸(mesulfenfos)、美氟腙(metaflumizone)、滅達樂(metalaxyl)、滅達樂-M(metalaxyl-M)、聚乙醛(metaldehyde)、斯美地
(metam)、斯美地-銨(metam-ammonium)、噁唑醯草胺(metamifop)、苯嗪草酮(metamitron)、斯美地-鉀(metam-potassium)、斯美地-鈉(metam-sodium)、滅草胺(metazachlor)、嗪吡嘧磺隆(metazosulfuron)、間氯敵菌酮(metazoxolon)、滅特座(metconazole)、甲基涕巴(metepa)、美氟拉隆(metflurazon)、甲基苯噻隆(methabenzthiazuron)、蟲蟎畏(methacrifos)、美索丙鉑林(methalpropalin)、達馬松(methamidophos)、滅速克(methasulfocarb)、滅草唑(methazole)、呋菌胺(methfuroxam)、滅大松(methidathion)、甲硫苯卡(methiobencarb)、滅賜克(methiocarb)、甲硫嘧磺隆(methiopyrisulfuron)、甲硫涕巴(methiotepa)、麥瑟唑林(methiozolin)、滅草恆(methiuron)、蟲殺乙烯磷(methocrotophos)、醚草通(methometon)、納乃得(methomyl)、美賜平(methoprene)、美保嗪(methoprotryne)、喹啉羧酸-丁基(methoquin-butyl)、甲醚菊酯(methothrin)、甲氧氯(methoxychlor)、滅芬諾(methoxyfenozide)、去草酮(methoxyphenone)、甲基唑磷嗪(methyl apholate)、溴甲烷(methyl bromide)、甲基丁香粉(methyl eugenol)、碘甲烷(methyl iodide)、異硫氰酸甲酯(methyl isothiocyanate)、甲基乙酯磷(methylacetophos)、甲基氯仿(methylchloroform)、甲基汰草龍(methyldymron)、二氯甲烷、甲基汞苯甲酸鹽(methylmercury benzoate)、甲基汞二氰二醯胺(methylmercury dicyandiamide)、甲基汞五氯酚鹽(methylmercury pentachlorophenoxide)、亞甲癸醯胺
(methylneodecanamide)、免得爛(metiram)、吡喃隆(metobenzuron)、撲奪草(metobromuron)、甲氧苄氟菊酯(metofluthrin)、莫多草(metolachlor)、治滅蝨(metolcarb)、苯氧菌胺(metominostrobin)、磺草唑胺(metosulam)、噁蟲酮(metoxadiazone)、甲氧隆(metoxuron)、滅芬農(metrafenone)、滅畢淨(metribuzin)、噻菌胺(metsulfovax)、甲磺隆(metsulfuron)、甲磺隆-甲基(metsulfuron-methyl)、美文松(mevinphos)、茲克威(mexacarbate)、邁森(mieshuan)、密滅汀(milbemectin)、倍脈心肟(milbemycin oxime)、代森環(milneb)、丙胺氟磷(mipafox)、滅蟻靈(mirex)、MNAF、蘑菇醇(moguchun)、稻得壯(molinate)、殺蟲單(molosultap)、庚草利(monalide)、莫尼索隆(monisouron)、一氯乙酸、亞素靈(monocrotophos)、綠穀隆(monolinuron)、單嘧磺隆(monosulfuron)、單嘧磺隆-酯(monosulfuron-ester)、滅草隆(monuron)、滅草隆TCA(monuron TCA)、伐草快(morfamquat)、伐草快二氯化物(morfamquat dichloride)、嗎啉胍(moroxydine)、嗎啉胍鹽酸鹽(moroxydine hydrochloride)、茂果(morphothion)、墨茲(morzid)、莫昔克丁(moxidectin)、MSMA、誘蟲烯(muscalure)、邁克尼(myclobutanil)、米克啉(myclozolin)、(N-(乙基汞)-對甲苯磺醯苯胺)、代森鈉(nabam)、萘肽磷(naftalofos)、乃力松(naled)、萘、萘乙醯胺、萘酐、萘氧乙酸、萘普草(naproanilide)、滅落脫(napropamide)、納得爛(naptalam)、納得爛-鈉(naptalam-sodium)、那他黴素
(natamycin)、草不隆(neburon)、氯硝柳胺(niclosamide)、氯硝柳胺-醇胺(niclosamide-olamine)、菸嘧磺隆(nicosulfuron)、菸鹼(nicotine)、伏蟻靈(nifluridide)、尼平拉芬(nipyraclofen)、烯啶蟲胺(nitenpyram)、硝基亞秦(nithiazine)、滅殺草(nitralin)、氯啶(nitrapyrin)、戊腈威(nitrilacarb)、除草醚(nitrofen)、三氟甲草醚(nitrofluorfen)、硝苯乙烯(nitrostyrene)、酞菌酯-異丙基(nitrothal-isopropyl)、鼠特靈(norbormide)、氟草敏(norflurazon)、降菸鹼(nornicotine)、草完隆(noruron)、諾瓦隆(novaluron)、紐伏隆(noviflumuron)、尼瑞莫(nuarimol)、OCH、八氯二丙基醚、辛噻酮(octhilinone)、呋醯胺(ofurace)、毆滅松(omethoate)、坪草丹(orbencarb)、歐弗拉洛(orfralure)、鄰-二氯苯、嘧苯胺磺隆(orthosulfamuron)、歐塔路(oryctalure)、肟醚菌胺(orysastrobin)、毆拉靈(oryzalin)、奧斯索(osthol)、歐斯措莫(ostramone)、解草腈(oxabetrinil)、丙炔噁草酮(oxadiargyl)、樂滅草(oxadiazon)、歐殺斯(oxadixyl)、草氨酸酯(oxamate)、歐殺滅(oxamyl)、草噠松(oxapyrazon)、草噠松-載莫胺(oxapyrazon-dimolamine)、草噠松-鈉(oxapyrazon-sodium)、環氧嘧磺隆(oxasulfuron)、噁嗪草酮(oxaziclomefone)、快得寧(oxine-copper)、歐索林酸(oxolinic acid)、惡咪唑(oxpoconazole)、惡咪唑反丁烯二酸鹽(oxpoconazole fumarate)、嘉保信(oxycarboxin)、碸吸磷-甲基(oxydemeton-methyl)、異亞碸磷(oxydeprofos)、碸拌磷
(oxydisulfoton)、復祿芬(oxyfluorfen)、氧化苦參鹼(oxymatrine)、土黴素(oxytetracycline)、土黴素鹽酸鹽(oxytetracycline hydrochloride)、巴克素(paclobutrazol)、哌蟲啶(paichongding)、對二氯苯、對氟隆(parafluron)、巴拉刈(paraquat)、巴拉刈二氯化物(paraquat dichloride)、巴拉刈二甲基硫酸鹽(paraquat dimetilsulfate)、巴拉松(parathion)、巴拉松-甲基(parathion-methyl)、苯吡醇(parinol)、克草敵(pebulate)、披扶座(pefurazoate)、壬酸(pelargonic acid)、平克座(penconazole)、賓克隆(pencycuron)、施得圃(pendimethalin)、賓氟芬(penflufen)、氟幼脲(penfluron)、平速爛(penoxsulam)、五氯苯酚(pentachlorophenol)、蔬草滅(pentanochlor)、吡噻菌胺(penthiopyrad)、百滅寧(pentmethrin)、環戊惡草酮(pentoxazone)、黃草伏(perfluidone)、百滅寧(permethrin)、烯草胺(pethoxamid)、氰烯菌胺(phenamacril)、葉枯淨(phenazine oxide)、棉胺寧(phenisopham)、芬硫磷(phenkapton)、甜菜寧(phenmedipham)、甜菜寧-乙基(phenmedipham-ethyl)、醯草隆(phenobenzuron)、酚丁滅蝨(phenothrin)、苯蟎醚(phenproxide)、賽達松(phenthoate)、苯基汞脲(phenylmercuriurea)、苯基汞乙酸鹽(phenylmercury acetate)、苯基汞氯化物(phenylmercury chloride)、焦兒茶酚之苯基汞衍生物(phenylmercury derivative of pyrocatechol)、硝酸苯汞(phenylmercury nitrate)、苯基汞水楊酸鹽(phenylmercury salicylate)、福瑞
松(phorate)、毒鼠磷(phosacetim)、裕必松(phosalone)、氯瘟磷(phosdiphen)、棉安磷(phosfolan)、棉安磷-甲基(phosfolan-methyl)、甘胺硫磷(phosglycin)、益滅松(phosmet)、對氯硫磷(phosnichlor)、福賜米松(phosphamidon)、膦、(phosphocarb)、磷、三磷錫(phostin)、巴賽松(phoxim)、巴賽松-甲基(phoxim-methyl)、苯酞(phthalide)、畢克爛(picloram)、畢克爛-2-乙基己基(picloram-2-ethylhexyl)、畢克爛-異辛基(picloram-isoctyl)、畢克爛-甲基(picloram-methyl)、畢克爛-醇胺(picloram-olamine)、畢克爛-鉀(picloram-potassium)、畢克爛-三乙銨(picloram-triethylammonium)、畢克爛-參(2-羥丙基)銨(picloram-tris(2-hydroxypropyl)ammonium)、氟吡草胺(picolinafen)、啶氧菌胺(picoxystrobin)、殺鼠酮(pindone)、殺鼠酮-鈉(pindone-sodium)、唑啉草酯(pinoxaden)、粉病靈(piperalin)、胡椒基丁醚(piperonyl butoxide)、胡椒基環己烯酮(piperonyl cyclonene)、哌草磷(piperophos)、哌壯素(piproctanyl)、哌壯素溴化物(piproctanyl bromide)、增效醛(piprotal)、甲胺基嘧啶磷(pirimetaphos)、比加普(pirimicarb)、嘧啶氧磷(pirimioxyphos)、蟲蟎磷-乙基(pirimiphos-ethyl)、蟲蟎磷-甲基(pirimiphos-methyl)、三氯殺蟲酯(plifenate)、聚胺基甲酸酯(polycarbamate)、保粒菌素(polyoxins)、多氧菌素(polyoxorim)、多氧菌素-鋅(polyoxorim-zinc)、多噻烷(polythialan)、亞砷酸鉀(potassium arsenite)、疊氮鉀(potassium azide)、氰酸鉀(potassium
cyanate)、赤黴酸鉀(potassium gibberellate)、環烷酸鉀(potassium naphthenate)、多硫化鉀(potassium polysulfide)、硫氰酸鉀(potassium thiocyanate)、α-萘乙酸鉀(potassium α-naphthaleneacetate)、pp'-DDT、炔丙菊酯(prallethrin)、早熟素I(precocene I)、早熟素II(precocene II)、早熟素III(precocene III)、普拉草(pretilachlor)、乙醯嘧啶磷(primidophos)、氟嘧磺隆(primisulfuron)、氟嘧磺隆-甲基(primisulfuron-methyl)、撲殺熱(probenazole)、撲克拉(prochloraz)、撲克拉-錳(prochloraz-manganese)、丙氯醇(proclonol)、丙噻嗪(procyazine)、撲滅寧(procymidone)、苯胺靈(prodiamine)、佈飛松(profenofos)、氟唑草胺(profluazol)、環丙氟靈(profluralin)、丙氟菊酯(profluthrin)、環苯草酮(profoxydim)、甘撲津(proglinazine)、甘撲津-乙基(proglinazine-ethyl)、調環酸(prohexadione)、調環酸-鈣(prohexadione-calcium)、茉莉酮(prohydrojasmon)、蜱虱威(promacyl)、猛殺威(promecarb)、撲滅通(prometon)、佈滅淨(prometryn)、捕滅鼠(promurit)、雷蒙得(propachlor)、普羅帕脒(propamidine)、普羅帕脒二鹽酸鹽(propamidine dihydrochloride)、普拔克(propamocarb)、普拔克鹽酸鹽(propamocarb hydrochloride)、除草靈(propanil)、丙蟲磷(propaphos)、普拔草(propaquizafop)、毆蟎多(propargite)、撲蟲菊(proparthrin)、普拔根(propazine)、巴胺磷(propetamphos)、苯胺靈(propham)、普克利(propiconazole)、甲基鋅乃浦(propineb)、異丙草胺(propisochlor)、安丹
(propoxur)、丙氧磺隆(propoxycarbazone)、丙氧磺隆-鈉(propoxycarbazone-sodium)、丙基增效劑(propyl isome)、嗪咪唑嘧磺隆(propyrisulfuron)、戊炔草胺(propyzamide)、丙氧喹啉(proquinazid)、骨酯素(prosuler)、甲硫磺樂靈(prosulfalin)、苄草丹(prosulfocarb)、氟磺隆(prosulfuron)、乙噻唑磷(prothidathion)、胺丙威(prothiocarb)、胺丙威鹽酸鹽(prothiocarb hydrochloride)、丙硫菌唑(prothioconazole)、普硫松(prothiofos)、發果(prothoate)、丙苯烴菊酯(protrifenbute)、撲滅生(proxan)、撲滅生-鈉(proxan-sodium)、丙炔草胺(prynachlor)、皮丹能(pydanon)、派滅淨(pymetrozine)、吡喃靈(pyracarbolid)、吡唑硫磷(pyraclofos)、雙唑草腈(pyraclonil)、百克敏(pyraclostrobin)、吡草醚(pyraflufen)、吡草醚乙酯(pyraflufen-ethyl)、吡氟普羅(pyrafluprole)、嘧啶威(pyramat)、唑胺菌酯(pyrametostrobin)、唑菌酯(pyraoxystrobin)、磺醯草吡唑(pyrasulfotole)、比拉唑諾(pyrazolynate)、白粉松(pyrazophos)、吡嘧磺隆(pyrazosulfuron)、吡嘧磺隆-乙基(pyrazosulfuron-ethyl)、彼硫磷(pyrazothion)、普芬草(pyrazoxyfen)、苄呋菊酯(pyresmethrin)、除蟲菊酯I(pyrethrin I)、除蟲菊酯II(pyrethrin II)、除蟲菊酯類(pyrethrins)、草醚-異丙基(pyribambenz-isopropyl)、草醚-丙基(pyribambenz-propyl)、吡瑞苯卡(pyribencarb)、嘧啶肟草醚(pyribenzoxim)、稗草畏(pyributicarb)、氯草定(pyriclor)、畢達本(pyridaben)、吡
啶達醇(pyridafol)、啶蟲丙醚(pyridalyl)、必芬松(pyridaphenthion)、必汰草(pyridate)、啶菌腈(pyridinitril)、比芬諾(pyrifenox)、哌氟喹腙(pyrifluquinazon)、環酯草醚(pyriftalid)、派美尼(pyrimethanil)、畢汰芬(pyrimidifen)、嘧草醚(pyriminobac)、嘧草醚-甲基(pyriminobac-methyl)、嘧啶硫蕃(pyrimisulfan)、嘧硫磷(pyrimitate)、滅鼠優(pyrinuron)、甲氧苯啶菌(pyriofenone)、皮瑞普(pyriprole)、吡啶醇(pyripropanol)、百利普芬(pyriproxyfen)、嘧硫草醚(pyrithiobac)、嘧硫草醚-鈉(pyrithiobac-sodium)、吡唑威(pyrolan)、百快隆(pyroquilon)、派羅克殺草碸(pyroxasulfone)、甲氧磺草胺(pyroxsulam)、氯甲氧吡啶(pyroxychlor)、吡氧呋(pyroxyfur)、苦木(quassia)、喹烯酮(quinacetol)、喹烯酮硫酸鹽(quinacetol sulfate)、拜裕松(quinalphos)、拜裕松-甲基(quinalphos-methyl)、醌菌腙(quinazamid)、快克草(quinclorac)、喹唑(quinconazole)、喹草酸(quinmerac)、滅藻醌(quinoclamine)、氯藻胺(quinonamid)、畜寧磷(quinothion)、快諾芬(quinoxyfen)、喹硫磷(quintiofos)、五氯硝基苯(quintozene)、快伏草(quizalofop)、快伏草-乙基(quizalofop-ethyl)、快伏草-P(quizalofop-P)、快伏草-P-乙基(quizalofop-P-ethyl)、快伏草-P-提夫里(quizalofop-P-tefuryl)、驅蚊酯(quwenzhi)、驅蠅啶(quyingding)、吡咪唑(rabenzazole)、碘醚柳胺(rafoxanide)、二乙基苯甲醯胺(rebemide)、苄呋菊酯(resmethrin)、硫氰苯胺(rhodethanil)、鬧羊花毒素
-III(rhodojaponin-III)、病毒唑(ribavirin)、碸嘧磺隆(rimsulfuron)、魚藤精(rotenone)、魚尼汀(ryania)、索氟納西(saflufenacil)、噻菌茂(saijunmao)、噻森銅(saisentong)、水楊苯胺(salicylanilide)、血根鹼(sanguinarine)、山道年(santonin)、八甲磷(schradan)、海蔥糖苷(scilliroside)、塞佈拉嗪(sebuthylazine)、密草通(secbumeton)、塞達生(sedaxane)、西拉菌素(selamectin)、單甲咪(semiamitraz)、單甲咪氯化物(semiamitraz chloride)、增效菊(sesamex)、芝麻啉(sesamolin)、西殺草(sethoxydim)、雙甲胺草磷(shuangjiaancaolin)、環草隆(siduron)、誘蟲環(siglure)、矽護芬(silafluofen)、雜氮矽三環(silatrane)、矽膠(silica gel)、矽硫芬(silthiofam)、草滅淨(simazine)、矽氟唑(simeconazole)、西默通(simeton)、西草淨(simetryn)、殺雄啉(sintofen)、SMA、S-莫多草(S-metolachlor)、亞砷酸鈉、疊氮化鈉(sodium azide)、氯酸鈉、氟化鈉、氟乙酸鈉、六氟矽酸鈉、環烷酸鈉(sodium naphthenate)、鄰苯基苯酚化鈉(sodium orthophenylphenoxide)、五氯酚鈉(sodium pentachlorophenoxide)、多硫化鈉(sodium polysulfide)、硫氰酸鈉(sodium thiocyanate)、α-萘乙酸鈉(sodium α-naphthaleneacetate)、蘇果(sophamide)、賜諾特(spinetoram)、賜諾殺(spinosad)、賜派芬(spirodiclofen)、螺甲蟎酯(spiromesifen)、賜派滅(spirotetramat)、螺環菌胺(spiroxamine)、鏈黴素(streptomycin)、鏈黴素倍半硫酸鹽(streptomycin sesquisulfate)、番木鼈鹼(strychnine)、食菌甲
誘醇(sulcatol)、舒可夫隆(sulcofuron)、舒可夫隆-鈉(sulcofuron-sodium)、磺草酮(sulcotrione)、菜草畏(sulfallate)、甲磺草胺(sulfentrazone)、舒非侖(sulfiram)、氯蟲胺(sulfluramid)、甲嘧磺隆(sulfometuron)、甲嘧磺隆-甲基(sulfometuron-methyl)、磺嘧磺隆(sulfosulfuron)、治螟磷(sulfotep)、氟啶蟲胺腈(sulfoxaflor)、亞碸(sulfoxide)、硫肟磷(sulfoxime)、硫、硫酸、硫醯氟(sulfuryl fluoride)、蘇格力卡品(sulglycapin)、硫丙磷(sulprofos)、戊苯碸(sultropen)、滅草靈(swep)、福化利(tau-fluvalinate)、稗草烯(tavron)、噻蟎威(tazimcarb)、TCA、TCA-銨、TCA-鈣、TCA-乙二基、TCA-鎂、TCA-鈉、TDE、得克利(tebuconazole)、得芬諾(tebufenozide)、吡蟎胺(tebufenpyrad)、異丁乙氧喹啉(tebufloquin)、丁基嘧啶磷(tebupirimfos)、胺草磷(tebutam)、得匍隆(tebuthiuron)、克枯爛(tecloftalam)、四氯硝基苯(tecnazene)、福美雙聯(tecoram)、得福隆(teflubenzuron)、七氟菊酯(tefluthrin)、特福三酮(tefuryltrione)、環磺酮(tembotrione)、亞培松(temephos)、替哌(tepa)、TEPP、得殺草(tepraloxydim)、環戊烯丙菊酯(terallethrin)、特草定(terbacil)、芽根靈(terbucarb)、特丁草胺(terbuchlor)、託福松(terbufos)、甲氧去草淨(terbumeton)、特丁津(terbuthylazine)、去草淨(terbutryn)、四環唑(tetcyclacis)、四氯乙烷(tetrachloroethane)、樂本松(tetrachlorvinphos)、四克利(tetraconazole)、得脫蟎(tetradifon)、四氟隆(tetrafluron)、
胺菊酯(tetramethrin)、四氟醚菊酯(tetramethylfluthrin)、四胺、四抗菌素(tetranactin)、殺蟎好(tetrasul)、硫酸鉈、欣克草(thenylchlor)、θ-氯氰菊酯(theta-cypermethrin)、腐絕(thiabendazole)、賽果培(thiacloprid)、氯噻亞菌胺(thiadifluor)、賽速安(thiamethoxam)、噻蟲腈(thiapronil)、噻氟隆(thiazafluron)、噻草啶(thiazopyr)、苯噻硫磷(thicrofos)、噻菌腈(thicyofen)、噻達茲明(thidiazimin)、噻苯隆(thidiazuron)、噻酮磺隆(thiencarbazone)、噻酮磺隆-甲基(thiencarbazone-methyl)、噻吩磺隆(thifensulfuron)、噻吩磺隆-甲基(thifensulfuron-methyl)、賽氟滅(thifluzamide)、殺丹(thiobencarb)、抗蟲威(thiocarboxime)、硫氯苯亞胺(thiochlorfenphim)、硫賜安(thiocyclam)、硫賜安鹽酸鹽(thiocyclam hydrochloride)、硫賜安草酸鹽(thiocyclam oxalate)、噻菌-銅(thiodiazole-copper)、硫敵克(thiodicarb)、硫伐隆(thiofanox)、硫氟肟(thiofluoximate)、不育硫磷(thiohempa)、硫柳汞(thiomersal)、硫滅松(thiometon)、硫磷嗪(thionazin)、多保淨(thiophanate)、甲基多保淨(thiophanate-methyl)、克殺蟎(thioquinox)、胺基硫脲(thiosemicarbazide)、殺蟲雙(thiosultap)、殺蟲雙-二銨(thiosultap-diammonium)、殺蟲雙-二鈉(thiosultap-disodium)、殺蟲雙-單鈉(thiosultap-monosodium)、噻替派(thiotepa)、得恩地(thiram)、蘇力菌素(thuringiensin)、汰敵寧(tiadinil)、調劑胺(tiaojiean)、仲草丹(tiocarbazil)、賽克林(tioclorim)、噻噁
米(tioxymid)、威線肟(tirpate)、脫克松(tolclofos-methyl)、脫芬瑞(tolfenpyrad)、甲基益發靈(tolylfluanid)、甲苯汞乙酸鹽(tolylmercury acetate)、苯吡唑草酮(topramezone)、苯草酮(tralkoxydim)、溴氯氰菊酯(tralocythrin)、泰滅甯(tralomethrin)、曲洛比利(tralopyril)、四氟苯菊酯(transfluthrin)、反氯菊酯(transpermethrin)、曲他胺(tretamine)、三十烷醇(triacontanol)、三泰芬(triadimefon)、三泰隆(triadimenol)、氟酮磺草胺(triafamone)、野麥畏(tri-allate)、三唑磷胺(triamiphos)、抑芽唑(triapenthenol)、苯蟎噻(triarathene)、嘧菌醇(triarimol)、醚苯磺隆(triasulfuron)、唑蚜威(triazamate)、丁三唑(triazbutil)、三嗪氟草胺(triaziflam)、三落松(triazophos)、咪唑嗪(triazoxide)、苯磺隆(tribenuron)、苯磺隆-甲基(tribenuron-methyl)、脫葉磷(tribufos)、氧化三丁基錫(tributyltin oxide)、殺草畏(tricamba)、水楊菌胺(trichlamide)、三氯松(trichlorfon)、三氯偏磷酸-3(trichlormetaphos-3)、壤蟲磷(trichloronat)、三氯比(triclopyr)、三氯比-丁氧基乙酯(triclopyr-butotyl)、三氯比-乙基(triclopyr-ethyl)、三氯比-三乙銨(triclopyr-triethylammonium)、三賽唑(tricyclazole)、三得芬(tridemorph)、滅草環(tridiphane)、草達津(trietazine)、蝸螺殺(trifenmorph)、三氯丙氧磷(trifenofos)、三氟敏(trifloxystrobin)、三氟啶磺隆(trifloxysulfuron)、三氟啶磺隆鈉(trifloxysulfuron-sodium)、賽福座(triflumizole)、殺蟲
隆(triflumuron)、三福林(trifluralin)、氟胺磺隆(triflusulfuron)、氟胺磺隆-甲基(triflusulfuron-methyl)、特立弗(trifop)、特立弗-甲基(trifop-methyl)、三氟禾草肟(trifopsime)、賽福寧(triforine)、三羥基三嗪(trihydroxytriazine)、誘蠅羧酯(trimedlure)、混滅威(trimethacarb)、三甲隆(trimeturon)、抗倒酯(trinexapac)、抗倒酯-乙基(trinexapac-ethyl)、烯蟲硫酯(triprene)、三丙丹(tripropindan)、雷公藤甲素(triptolide)、草達克(tritac)、滅菌唑(triticonazole)、三氟甲磺隆(tritosulfuron)、特朗扣(trunc-call)、單克素(uniconazole)、單克素-P(uniconazole-P)、福美甲胂(urbacide)、烏瑞替派(uredepa)、戊酸酯(valerate)、維利黴素(validamycin)、伐利芬那(valifenalate)、異殺鼠酮(valone)、繁米松(vamidothion)、泛佳(vangard)、萬尼普(vaniliprole)、萬隆(vernolate)、免克寧(vinclozolin)、華法林(warfarin)、華法林-鉀(warfarin-potassium)、華法林-鈉(warfarin-sodium)、硝蟲硫磷(xiaochongliulin)、辛菌胺(xinjunan)、烯肟菌胺(xiwojunan)、XMC、二甲苯草胺(xylachlor)、二甲苯酚(xylenols)、滅爾蝨(xylylcarb)、依希淨(yishijing)、氰菌胺(zarilamid)、玉米素(zeatin)、增效胺(zengxiaoan)、ζ-氯氰菊酯(zeta-cypermethrin)、環烷酸鋅(zinc naphthenate)、磷化鋅(zinc phosphide)、噻唑鋅(zinc thiazole)、鋅乃浦(zineb)、福美鋅(ziram)、丙硫噁唑磷(zolaprofos)、座賽胺(zoxamide)、唑嘧磺隆(zuomihuanglong)、α-氯醇
(α-chlorohydrin)、α-蛻皮激素(α-ecdysone)、α-多紋素(α-multistriatin)及α-萘乙酸(α-naphthaleneacetic acid)。對於更多資訊,查閱位於http://www.alanwood.net/pesticides/index.html之「COMPENDIUM OF PESTICIDE COMMON NAMES」。亦查閱「THE PESTICIDE MANUAL」第14版,由C D S Tomlin編輯,British Crop Production Council 2006版權所有,或其先前或更近版本。
生物殺蟲劑
式I分子亦可與一或多種生物殺蟲劑組合(諸如以組合混合物、或同時或依序施用形式)使用。「生物殺蟲劑」一詞用於按與化學殺蟲劑相似之方式施用之微生物生物害蟲控制劑。通常,此等為細菌控制劑,但亦有真菌控制劑之實例,包括木黴屬(Trichoderma spp.)及白粉寄生孢(Ampelomyces quisqualis)(用於葡萄白粉病(grape powdery mildew)之控制劑)。枯草桿菌(Bacillus subtilis)用於控制植物病原體。雜草及嚙齒動物亦已用微生物劑控制。一種熟知的殺蟲劑實例為蘇力菌(Bacillus thuringiensis),一種鱗翅目(Lepidoptera)、鞘翅目(Coleoptera)及雙翅目(Diptera)之細菌性疾病。由於其對其他生物幾乎不具有作用,所以認為其相比於合成殺蟲劑更為環境友善的。生物殺蟲劑包括基於以下之產物:1.昆蟲病原真菌(例如金龜子綠僵菌(Metarhizium anisopliae));
2.昆蟲病原線蟲(例如夜蛾斯氏線蟲(Steinernema feltiae));及3.昆蟲病原病毒(例如蘋果蠹蛾顆粒體病毒(Cydia pomonella granulovirus))。
昆蟲病原有機體之其他實例包括(但不限於)桿狀病毒、細菌及其他原核生物、真菌、原生動物及微孢子蟲(Microsproridia)。生物學衍生之殺昆蟲劑包括(但不限於)魚藤精、藜蘆定以及微生物毒素;耐昆蟲或抗昆蟲之植物品種;及藉由重組DNA技術修飾之有機體,從而產生殺昆蟲劑或將抗昆蟲性質運送至經遺傳修飾之有機體上。在一個實施例中,式I分子可與一或多種生物殺蟲劑一起用於種子處理及土壤改良領域。The Manual of Biocontrol Agents給出可利用之生物殺昆蟲劑(及其他基於生物之控制)產物之評介。Copping L.G.(編)(2004).The Manual of Biocontrol Agents(先前為the Biopesticide Manual)第3版.British Crop Production Council(BCPC),Farnham,Surrey UK。
其他活性化合物
式I分子亦可與以下中之一或多者組合(諸如以組合混合物、或同時或依序施用形式)使用:1. 3-(4-氯-2,6-二甲基苯基)-4-羥基-8-氧雜-1-氮雜螺[4,5]癸-3-烯-2-酮;2. 3-(4'-氯-2,4-二甲基[1,1'-聯苯]-3-基)-4-羥基-8-氧雜-1-氮雜螺[4,5]癸-3-烯-2-酮;3. 4-[[(6-氯-3-吡啶基)甲基]甲基胺基]-2(5H)-呋喃酮;
4. 4-[[(6-氯-3-吡啶基)甲基]環丙基胺基]-2(5H)-呋喃酮;5. 3-氯-N2-[(1S)-1-甲基-2-(甲基磺醯基)乙基]-N1-[2-甲基-4-[1,2,2,2-四氟-1-(三氟甲基)乙基]苯基]-1,2-苯二甲醯胺;6. 2-氰基-N-乙基-4-氟-3-甲氧基-苯磺醯胺;7. 2-氰基-N-乙基-3-甲氧基-苯磺醯胺;8. 2-氰基-3-二氟甲氧基-N-乙基-4-氟-苯磺醯胺;9. 2-氰基-3-氟甲氧基-N-乙基-苯磺醯胺;10. 2-氰基-6-氟-3-甲氧基-N,N-二甲基-苯磺醯胺;11. 2-氰基-N-乙基-6-氟-3-甲氧基-N-甲基-苯磺醯胺;12. 2-氰基-3-二氟甲氧基-N,N-二甲基苯磺醯胺;13. 3-(二氟甲基)-N-[2-(3,3-二甲基丁基)苯基]-1-甲基-1H-吡唑-4-甲醯胺;14. N-乙基-2,2-二甲基丙醯胺-2-(2,6-二氯-α,α,α-三氟-對甲苯基)腙;15. N-乙基-2,2-二氯-1-甲基環丙烷-甲醯胺-2-(2,6-二氯-α,α,α-三氟-對甲苯基)腙菸鹼;16. 硫碳酸O-{(E-)-[2-(4-氯-苯基)-2-氰基-1-(2-三氟甲基苯基)-乙烯基]}酯S-甲酯;17. (E)-N1-[(2-氯-1,3-噻唑-5-基甲基)]-N2-氰基-N1-甲基乙脒;18. 1-(6-氯吡啶-3-基甲基)-7-甲基-8-硝基-1,2,3,5,6,7-六氫-咪唑并[1,2-a]吡啶-5-醇;
19. 甲磺酸4-[4-氯苯基-(2-次丁基-亞肼基)甲基)]苯酯;及20. N-乙基-2,2-二氯-1-甲基環丙烷甲醯胺-2-(2,6-二氯-α,α,α-三氟-對甲苯基)腙。
協同混合物
式I分子可與某些活性化合物一起使用以形成協同混合物,其中該等化合物之作用模式相比於式I分子之作用模式為相同、相似或不同的。作用模式之實例包括(但不限於):乙醯膽鹼酯酶抑制劑;鈉通道調節劑;甲殼素生物合成抑制劑;GABA及麩胺酸鹽閘控氯化物通道拮抗劑;GABA及麩胺酸鹽閘控氯化物通道促效劑;乙醯膽鹼受體促效劑;乙醯膽鹼受體拮抗劑;MET I抑制劑;Mg刺激ATP酶抑制劑;菸鹼性乙醯膽鹼受體;中腸膜干擾劑;氧化磷酸化干擾劑及羅納丹受體(ryanodine receptor;RyR)。一般而言,協同混合物中之式I分子與另一化合物之重量比為約10:1至約1:10,在另一實施例中為約5:1至約1:5,且在另一實施例中為約3:1,且在另一實施例中為約1:1。
調配物
殺蟲劑幾乎不適於以其純形式來施用。通常需要添加其他物質,以便使殺蟲劑可按所需濃度及適當形式來使用,允許輕易施用、處理、運輸、儲存及最大殺蟲劑活性。因此,將殺蟲劑調配成例如誘餌、濃縮乳液、塵劑、可乳化濃縮物、薰蒸劑、凝膠、顆粒、微膠囊、種子處理、懸浮濃縮物、懸浮乳液、錠劑、水溶性液體、水可分散顆
粒或乾燥可流動物、可濕性粉末及超低體積溶液。關於調配物類型之進一步資訊,參見「Catalogue of Pesticide Formulation Types and International Coding System」Technical Monograph n°2,第5版CropLife International(2002)。
殺蟲劑最經常以由該等殺蟲劑之經濃縮調配物製備之水性懸浮液或乳液之形式來施用。該等水溶性、水可懸浮或可乳化調配物為固體(通常稱為可濕性粉末或水可分散顆粒)或液體(通常稱為可乳化濃縮物或水性懸浮液)。可濕性粉末(其可經壓緊以形成水可分散顆粒)包含殺蟲劑、載劑及界面活性劑之緊密混合物。殺蟲劑之濃度通常為約10重量%至約90重量%。載劑通常在鎂鋁海泡石黏土(attapulgite clay)、蒙脫土(montmorillonite clay)、矽藻土(diatomaceous earth)或經純化之矽酸鹽之中選擇。有效的界面活性劑(佔可濕性粉末之約0.5%至約10%)發現自磺化木質素、濃縮萘磺酸鹽、萘磺酸鹽、烷基苯磺酸鹽、烷基硫酸鹽及非離子界面活性劑(諸如烷基酚之環氧乙烷加成物)之中。
殺蟲劑之可乳化濃縮物包含溶解於載劑(該載劑為水可混溶的溶劑或水不混溶的有機溶劑及乳化劑之混合物)中之合宜濃度之殺蟲劑(諸如每公升液體約50至約500公克)。有用的有機溶劑包括芳族溶劑(尤其為二甲苯)及石油餾份(尤其為石油之高沸點萘部分及烯烴部分(諸如重芳族石腦油))。亦可使用其他有機溶劑,諸如萜烯溶劑(包括松
香衍生物)、脂族酮(諸如環己酮)及複雜醇(諸如2-乙氧基乙醇)。用於可乳化濃縮物之適合之乳化劑係選自習知陰離子界面活性劑及非離子界面活性劑。
水性懸浮液包含以在約5重量%至約50重量%範圍內之濃度分散在水性載劑中之水不溶性殺蟲劑的懸浮液。懸浮液藉由以下方式製備:精細研磨殺蟲劑並將其劇烈混合至載劑中,該載劑包含水及界面活性劑。亦可添加諸如無機鹽及合成膠或天然膠之成分,從而增加水性載劑之密度及黏度。通常最有效的為藉由在儀器(諸如砂磨機、球磨機或活塞型均質器)中製備水性混合物並對其進行均質化來同時研磨及混合殺蟲劑。
殺蟲劑亦可按顆粒組成物之形式來施用,該等顆粒組成物尤其適用於施用至土壤中。顆粒組成物通常含有分散在載劑中之約0.5重量%至約10重量%之殺蟲劑,該載劑包含黏土或相似物質。該等組成物通常藉由以下方式製備:將該殺蟲劑溶解在適合之溶劑中並將其施用至顆粒載劑上,該顆粒載劑已經預成形為適當粒徑(在約0.5至約3mm範圍內)。該等組成物亦可藉由以下方式調配:將該載劑及化合物製成麵團狀或糊狀,且壓碎並乾燥,從而得到所需顆粒粒徑。
含有殺蟲劑之塵劑藉由以下方式製備:將呈粉末形式之殺蟲劑與適合之粉塵狀農業載劑(諸如高嶺黏土、經研磨火山岩及其類似載劑)緊密混合。塵劑可適合地含有約1%至約10%殺蟲劑。其可應用於拌種或與粉塵鼓風機一起
用於葉面施用。
同樣可行的為施用含呈溶液形式之殺蟲劑之適當有機溶劑(通常為石油,諸如噴霧油),該有機溶劑廣泛用於農業化學。
殺蟲劑亦可按氣溶膠組成物之形式來施用。在該等組成物中,將殺蟲劑溶解或分散在載劑中,該載劑為產生壓力之推進劑混合物。將氣溶膠組成物包裝在容器中,該混合物經由霧化閥自該容器中分配。
當將殺蟲劑與食物或引誘劑或兩者混合時,形成殺蟲劑誘餌。當害蟲吃掉誘餌時,其亦消耗殺蟲劑。誘餌可呈顆粒、凝膠、可流動粉末、液體或固體形式。其亦可用於害蟲藏身處。
薰蒸劑為具有相對較高蒸氣壓之殺蟲劑,且因此可以濃度足以殺死土壤或密封空間中之害蟲的氣體形式存在。薰蒸劑之毒性與其濃度及曝露時間成比例。其特徵在於具有良好的擴散能力,並藉由滲透至害蟲之呼吸系統中或經由害蟲之表皮吸收來起作用。施用薰蒸劑以便在氣密房間或建築物中或在專門腔室中對防氣片(gas proof sheet)下之儲藏產品害蟲進行控制。
可藉由將殺蟲劑粒子或小滴懸浮在各種類型之塑膠聚合物中來對殺蟲劑進行微膠囊化。藉由改變聚合物之化學性質或藉由改變處理中之因素,可形成各種大小、溶解度、壁厚度及滲透度之微膠囊。此等因素控制其中活性成分之釋放速度,而釋放速度又影響產品之殘留效能、
作用速度及氣味。
藉由將殺蟲劑溶解於將使殺蟲劑維持於溶液中之溶劑中來製備油溶液濃縮物。殺蟲劑之油溶液由於溶劑本身具有殺蟲作用及體被之蠟質覆蓋物之溶解增加殺蟲劑的攝取速度而通常提供比其他調配物更快的擊倒及殺死害蟲作用。油溶液之其他優點包括較好的儲藏穩定性、更好的裂縫滲透性及更好的油膩表面黏附性。
另一實施例為水包油型乳劑,其中該乳劑包含油性小球,該等油性小球各自提供有層狀液晶塗層,並分散在水相中,其中各油性小球包含至少一種具有農業活性之化合物,並個別地塗佈有單層狀或寡層狀之層,該層包含:(1)至少一種非離子性親脂性界面活性劑、(2)至少一種非離子性親水性界面活性劑及(3)至少一種離子性界面活性劑,其中該等小球具有小於800奈米之平均粒徑。關於實施例之其他資訊揭示於2007年2月1日公開之具有專利申請案第11/495,228號之美國專利公開案20070027034中。為易於使用,此實施例將稱為「OIWE」。
對於其他資訊,查閱「Insect Pest Management」第2版D.Dent,CAB International(2000)版權所有。此外,對於更詳細資訊,查閱「Handbook of Pest Control-The Behavior,Life History,and Control of Household Pests」Arnold Mallis,第9版,GIE Media Inc 2004版權所有。
其他調配物組分
一般而言,當式I中揭示之分子用於調配物時,
該調配物亦可含有其他組分。此等組分包括(但不限於)(此為非窮舉性並且非相互排斥性之清單)潤濕劑、展佈劑、黏著劑、滲透劑、緩衝劑、螯合劑、漂浮降低劑、相容劑、消泡劑、清潔劑及乳化劑。接下來描述幾種組分。
潤濕劑為在將其添加至液體中時藉由降低液體與液體在其上展佈之表面之間的界面張力來增加液體的展佈或滲透力。潤濕劑用於農業化學調配物中之兩種主要功能:在處理及製造期間增加粉末在水中之潤濕速率從而製造可溶性液體之濃縮物或懸浮濃縮物;及在將產品與水在噴霧罐中混合期間降低可濕性粉末之潤濕時間並改善水向水可分散顆粒中之滲透。用於可濕性粉末、懸浮濃縮物及水可分散顆粒調配物中之潤濕劑之實例為:月桂基硫酸鈉、二辛基磺基丁二酸鈉、烷基酚乙氧化物及脂族醇乙氧化物。
分散劑為吸附至粒子表面上並有助於保持粒子之分散狀態以及防止粒子重新聚集的物質。將分散劑添加至農業化學調配物中以有助於製造期間之分散及懸浮,並且有助於確保粒子在噴霧罐中重新分散至水中。其廣泛用於可濕性粉末、懸浮濃縮物及水可分散顆粒中。用作分散劑之界面活性劑具有牢固吸附至粒子表面上之能力,並對粒子重新聚集提供電荷或空間障壁。最常用的界面活性劑為陰離子型、非離子型或該等兩種類型之混合物。對於可濕性粉末調配物,最常用分散劑為木質素磺酸鈉。對於懸浮濃縮物而言,使用聚電解質,諸如萘磺酸鈉甲醛濃縮物
來得到極好的吸附及穩定。亦使用三苯乙烯基苯酚乙氧化物磷酸酯。非離子物(諸如烷基芳基氧化乙烯濃縮物及EO-PO嵌段共聚物)有時與陰離子物組合起來作為用於懸浮濃縮物之分散劑。近年來,新型式之極高分子量聚合物界面活性劑已開發作為分散劑。此等具有極長之疏水性『主鏈』及大量氧化乙烯鏈,其形成『梳狀』界面活性劑之『齒』。此等高分子量聚合物可對懸浮濃縮物產生極好的長期穩定性,因為疏水性主鏈對粒子表面具有許多錨定點。用於農業化學調配物之分散劑之實例為:木質素磺酸鈉、萘磺酸鈉甲醛濃縮物、三苯乙烯基苯酚乙氧化物磷酸酯、脂族醇乙氧化物、烷基乙氧化物、EO-PO嵌段共聚物及接枝共聚物。
乳化劑為使一種液相之液滴於另一液相中之懸浮液穩定之物質。在無乳化劑之情況下,兩種液體會分離成兩個不混溶的液相。最常用的乳化劑摻合物含有具有12個或12個以上環氧乙烷單元之烷基酚或脂族醇及十二烷基苯磺酸之油溶性鈣鹽。8至18之範圍的親水親油平衡(「HLB」)值通常將提供良好穩定之乳液。乳液穩定性有時可藉由添加少量EO-PO嵌段共聚物界面活性劑來改進。
增溶劑為在濃度超過臨界膠束濃度時在水中形成膠束之界面活性劑。接著,膠束能夠在膠束之疏水部分內溶解或使水不溶性物質溶解。通常用於溶解作用之界面活性劑類型為非離子型、脫水山梨糖醇單油酸酯、脫水山梨糖醇單油酸酯乙氧化物及油酸甲酯。
界面活性劑有時單獨或與其他添加劑(諸如作為佐劑之礦物油或植物油)一起用於噴霧罐混合物,從而改進殺蟲劑對目標之生物效能。用於生物增強之界面活性劑類型通常視殺蟲劑之性質及作用模式而定。然而,其通常為非離子物,諸如:烷基乙氧化物;線性脂族醇乙氧化物;脂族胺乙氧化物。
農業調配物中之載劑或稀釋劑為添加至殺蟲劑中以得到所需強度產品之物質。載劑通常為具有較高吸收能力之物質,而稀釋劑通常為具有較低吸收能力之物質。載劑及稀釋劑用於塵劑、可濕性粉末、顆粒及水可分散顆粒之調配物。
有機溶劑主要用於可乳化濃縮物、水包油乳液、懸乳劑及超低體積調配物之調配物,及在較少程度上用於顆粒調配物。有時,使用溶劑混合物。第一主要群組之溶劑為脂族石蠟油,諸如煤油或精製石蠟。第二主要群組(且最常見)包含芳族溶劑,諸如二甲苯及較高分子量之C9及C10芳族溶劑之餾份。當將調配物乳化至水中時,氯化烴適用作防止殺蟲劑結晶之共溶劑。醇有時用作共溶劑以增強溶解力。其他溶劑可包括植物油,種子油及植物油與種子油之酯。
增稠劑或膠凝劑主要用於懸浮濃縮物、乳液及懸乳劑之調配物,以改變液體之流變學或流動性質及防止分散粒子或液滴分離及沈降。增稠劑、膠凝劑及抗沈降劑通常屬於兩種類別,亦即水不溶性微粒及水溶性聚合物。可
使用黏土及二氧化矽製造懸浮濃縮物調配物。此等物質類型之實例包括(但不限於):蒙脫石、膨潤土、矽酸鎂鋁及鎂鋁海泡石。水溶性多醣多年來已用作增稠膠凝劑。最常用之多醣類型為種子及海藻之天然萃取物或纖維素之合成衍生物。此等類型物質之實例包括(但不限於)瓜爾膠;刺槐豆膠;角叉菜膠;海藻酸鹽;甲基纖維素;羧甲基纖維素鈉(SCMC);羥乙基纖維素(HEC)。其他類型抗沈降劑係基於改質澱粉、聚丙烯酸酯、聚乙烯醇及聚氧化乙烯。另一良好抗沈降劑為三仙膠。
微生物可引起經配製產品之損壞。因此,防腐劑用於消除或降低其作用。該等試劑之實例包括(但不限於):丙酸及其鈉鹽;山梨酸及其鈉或鉀鹽;苯甲酸及其鈉鹽;對羥基苯甲酸鈉鹽;對羥基苯甲酸甲酯;及1,2-苯并異噻唑啉-3-酮(BIT)。
界面活性劑之存在經常引起水基調配物在製造及經由噴霧罐施用時在混合操作期間起泡。為了減少起泡之傾向,通常在製造階段期間或裝填至瓶中之前添加消泡劑。通常,存在兩種類型消泡劑,亦即聚矽氧及非聚矽氧。聚矽氧通常為二甲基聚矽氧烷之水性乳液,而非聚矽氧消泡劑為水不溶性油,諸如辛醇及壬醇,或二氧化矽。在兩種情況下,消泡劑之功能為自空氣-水界面中替換界面活性劑。
「綠色」試劑(例如佐劑、界面活性劑、溶劑)可降低作物保護調配物之整體環境足跡。綠色試劑為生物可
降解的,且通常衍生自天然及/或永續來源,例如植物及動物來源。特定實例為:植物油、種子油及其酯,亦為烷氧基化烷基聚葡糖苷。
對於進一步資訊,參見「Chemistry and Technology of Agrochemical Formulations」由D.A.Knowles編輯,Kluwer Academic Publishers 1998版權所有。亦參見「Insecticides in Agriculture and Environment-Retrospects and Prospects」A.S.Perry,I.Yamamoto,I.Ishaaya及R.Perry,Springer-Verlag 1998版權所有。
害蟲
一般而言,式I分子可用於控制害蟲,例如甲蟲、蠼螋、蟑螂、蒼蠅、蚜蟲、介殼蟲、粉虱、葉蟬、螞蟻、黃蜂、白蟻、蛾、蝴蝶、虱、蚱蜢、蝗蟲、蟋蟀、跳蚤、薊馬、衣魚、蟎、壁虱、線蟲及綜合蟲。
在另一實施例中,式I分子可用於控制線蟲動物門(Nematoda)及/或節肢動物門(Arthropoda)之害蟲。
在另一實施例中,式I分子可用於控制螯肢亞門(Chelicerata)、多足亞門(Myriapoda)及/或六足亞門(Hexapoda)之害蟲。
在另一實施例中,式I分子可用於控制蛛形綱(Arachnida)、綜合綱(Symphyla)及/或昆蟲綱(Insecta)之害蟲。
在另一實施例中,式I分子可用於控制虱目(Order Anoplura)之害蟲。特定屬之非窮舉性清單包括(但
不限於)血虱屬(Haematopinus spp.)、甲脅虱屬(Hoplopleura spp.)、顎虱屬(Linognathus spp.)、虱屬(Pediculus spp.)及鱗虱屬(Polyplax spp.)。特定物種之非窮舉性清單包括(但不限於)驢血虱(Haematopinus asini)、豬血虱(Haematopinus suis)、毛虱(Linognathus setosus)、綿羊顎虱(Linognathus ovillus)、人頭蝨(Pediculus humanus capitis)、人體虱(Pediculus humanus humanus)及陰虱(Pthirus pubis)。
在另一實施例中,式I分子可用於控制鞘翅目(Order Coleoptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)豆象屬(Acanthoscelides spp.)、叩頭蟲屬(Agriotes spp.)、花象屬(Anthonomus spp.)、梨象屬(Apion spp.)、金龜屬(Apogonia spp.)、守瓜屬(Aulacophora spp.)、豆象蟲屬(Bruchus spp.)、天牛屬(Cerosterna spp.)、豆葉甲蟲屬(Cerotoma spp.)、龜象屬(Ceutorhynchus spp.)、跳甲屬(Chaetocnema spp.)、肖葉甲蟲屬(Colaspis spp.)、梳瓜扣頭蟲屬(Ctenicera spp.)、象鼻蟲屬(Curculio spp.)、圓頭犀金龜屬(Cyclocephala spp.)、玉米根蟲屬(Diabrotica spp.)、葉象屬(Hypera spp.)、齒小蠹屬(Ips spp.)、粉蠹屬(Lyctus spp.)、美洲葉甲屬(Megascelis spp.)、菜花露尾甲蟲屬(Meligethes spp.)、鳥喙象屬(Otiorhynchus spp.)、玫瑰短喙象屬(Pantomorus spp.)、食葉鰓金龜屬(Phyllophaga spp.)、黃條跳甲屬(Phyllotreta spp.)、根鰓金龜屬(Rhizotrogus spp.)、梨象蟲屬(Rhynchites spp.)、隱頦象屬(Rhynchophorus spp.)、小蠹屬(Scolytus spp.)、禾象鼻蟲屬(Sphenophorus spp.)、米
象屬(Sitophilus spp.)及擬穀盜屬(Tribolium spp.)。特定物種之非窮舉性清單包括(但不限於)菜豆象(Acanthoscelides obtectus)、白蠟窄吉丁(Agrilus planipennis)、光肩星天牛(Anoplophora glabripennis)、棉鈴象蟲(Anthonomus grandis)、黑絨金龜(Ataenius spretulus)、甜菜隱食甲蟲(Atomaria linearis)、甜菜象(Bothynoderes punctiventris)、豌豆象(Bruchus pisorum)、四紋豆象(Callosobruchus maculatus)、黃斑露尾甲(Carpophilus hemipterus)、甜菜龜甲(Cassida vittata)、豆葉甲(Cerotoma trifurcata)、白菜籽龜象(Ceutorhynchus assimilis)、芫菁龜象(Ceutorhynchus napi)、梯斑叩頭蟲(Conoderus scalaris)、多斑叩頭蟲(Conoderus stigmosus)、李象(Conotrachelus nenuphar)、綠花金龜(Cotinis nitida)、石刁柏負泥蟲(Crioceris asparagi)、鏽赤扁穀盜(Cryptolestes ferrugineus)、長角扁穀盜(Cryptolestes pusillus)、土耳其扁穀盜(Cryptolestes turcicus)、密點細枝象蟲(Cylindrocopturus adspersus)、芒果剪葉象(Deporaus marginatus)、火腿皮蠹(Dermestes lardarius)、白腹皮蠹(Dermestes maculatus)、墨西哥豆瓢蟲(Epilachna varivestis)、蛀莖象甲(Faustinus cubae)、蒼白根頸象(Hylobius pales)、紫苜蓿葉象(Hypera postica)、咖啡果小蠹(Hypothenemus hampei)、菸草甲(Lasioderma serricorne)、馬鈴薯甲蟲(Leptinotarsa decemlineata)、麗金龜(Liogenys fuscus)、Liogenys suturalis、稻水象甲(Lissorhoptrus oryzophilus)、Maecolaspis joliveti、玉米叩甲
(Melanotus communis)、油菜花露尾甲(Meligethes aeneus)、五月金龜子(Melolontha melolontha)、梯頂天牛(Oberea brevis)、線性筒天牛(Oberea linearis)、椰蛀犀金龜(Oryctes rhinoceros)、貿易鋸穀盜(Oryzaephilus mercator)、鋸穀盜(Oryzaephilus surinamensis)、黑角負泥蟲(Oulema melanopus)、水稻負泥蟲(Oulema oryzae)、金龜子(Phyllophaga cuyabana)、日本弧麗金龜(Popillia japonica)、大穀蠹(Prostephanus truncatus)、穀蠹(Rhyzopertha dominica)、條紋根瘤象甲(Sitona lineatus)、穀象(Sitophilus granarius)、米象(Sitophilus oryzae)、玉米象(Sitophilus zeamais)、藥材甲(Stegobium paniceum)、赤擬穀盜(Tribolium castaneum)、雜擬穀盜(Tribolium confusum)、花斑皮蠹(Trogoderma variabile)及玉米距步甲蟲(Zabrus tenebrioides)。
在另一實施例中,式I分子可用於控制革翅目(Order Dermaptera)之害蟲。
在另一實施例中,式I分子可用於控制蜚蠊目(Order Blattaria)之害蟲。特定物種之非窮舉性清單包括(但不限於)德國小蠊(Blattella germanica)、東方蜚蠊(Blatta orientalis)、賓夕法尼亞木蠊(Parcoblatta pennsylvanica)、美洲大蠊(Periplaneta americana)、澳洲大蠊(Periplaneta australasiae)、棕色大蠊(Periplaneta brunnea)、菸色大蠊(Periplaneta fuliginosa)、蔗綠蜚蠊(Pycnoscelus surinamensis)及長鬚蜚蠊(Supella longipalpa)。
在另一實施例中,式I分子可用於控制雙翅目(Order Diptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)伊蚊屬(Aedes spp.)、潛蠅屬(Agromyza spp.)、按實蠅屬(Anastrepha spp.)、瘧蚊屬(Anopheles spp.)、果實蠅屬(Bactrocera spp.)、小條實蠅屬(Ceratitis spp.)、斑虻屬(Chrysops spp.)、錐蠅屬(Cochliomyia spp.)、癭蚊屬(Contarinia spp.)、庫蚊屬(Culex spp.)、葉癭蚊屬(Dasineura spp.)、地種蠅屬(Delia spp.)、果蠅屬(Drosophila spp.)、廁蠅屬(Fannia spp.)、黑蠅屬(Hylemyia spp.)、斑潛蠅屬(Liriomyza spp.)、蠅屬(Musca spp.)、草種蠅屬(Phorbia spp.)、牛虻屬(Tabanus spp.)及大蚊屬(Tipula spp.)。特定物種之非窮舉性清單包括(但不限於)紫苜蓿潛蠅(Agromyza frontella)、加勒比按實蠅(Anastrepha suspensa)、墨西哥按實蠅(Anastrepha ludens)、西印度按實蠅(Anastrepha obliqa)、瓜實蠅(Bactrocera cucurbitae)、桔小實蠅(Bactrocera dorsalis)、入侵實蠅(Bactrocera invadens)、桃實蠅(Bactrocera zonata)、地中海小條實蠅(Ceratitis capitata)、油菜葉癭蚊(Dasineura brassicae)、灰地種蠅(Delia platura)、黃腹廁蠅(Fannia canicularis)、灰腹廁蠅(Fannia scalaris)、腸胃蠅(Gasterophilus intestinalis)、Gracillia perseae、擾血蠅(Haematobia irritans)、紋皮蠅(Hypoderma lineatum)、菜潛蠅(Liriomyza brassicae)、綿羊虱蠅(Melophagus ovinus)、秋家蠅(Musca autumnalis)、家蠅(Musca domestica)、羊狂蠅(Oestrus ovis)、歐洲麥稈蠅
(Oscinella frit)、甜菜泉蠅(Pegomya betae)、胡蘿蔔莖蠅(Psila rosae)、櫻桃果蠅(Rhagoletis cerasi)、蘋果實蠅(Rhagoletis pomonella)、藍橘繞實蠅(Rhagoletis mendax)、麥紅吸漿蟲(Sitodiplosis mosellana)及廄螫蠅(Stomoxys calcitrans)。
在另一實施例中,式I分子可用於控制半翅目(Order Hemiptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)球蚜屬(Adelges spp.)、白輪盾蚧屬(Aulacaspis spp.)、沫蟬屬(Aphrophora spp.)、蚜蟲屬(Aphis spp.)、粉虱屬(Bemisia spp.)、蠟蚧屬(Ceroplastes spp.)、雪盾蚧屬(Chionaspis spp.)、圓盾蚧屬(Chrysomphalus spp.)、軟蠟蚧屬(Coccus spp.)、綠小葉蟬屬(Empoasca spp.)、蠣盾蚧屬(Lepidosaphes spp.)、蝽屬(Lagynotomus spp.)、草盲蝽屬(Lygus spp.)、長管蚜屬(Macrosiphum spp.)、黑尾葉蟬屬(Nephotettix spp.)、稻綠蝽屬(Nezara spp.)、沫蟬屬(Philaenus spp.)、植盲蝽屬(Phytocoris spp.)、壁蝽屬(Piezodorus spp.)、臀紋粉蚧屬(Planococcus spp.)、粉蚧屬(Pseudococcus spp.)、縊管蚜屬(Rhopalosiphum spp.)、珠蠟蚧屬(Saissetia spp.)、彩斑蚜屬(Therioaphis spp.)、蠟蚧蟲屬(Toumeyella spp.)、聲蚜屬(Toxoptera spp.)、粉虱屬(Trialeurodes spp.)、錐蝽屬(Triatoma spp.)及尖盾蚧屬(Unaspis spp.)。特定物種之非窮舉性清單包括(但不限於)擬綠蝽(Acrosternum hilare)、苜蓿豌豆蚜(Acyrthosiphon pisum)、甘藍粉虱(Aleyrodes proletella)、螺旋粉虱(Aleurodicus dispersus)、絲
絨粉虱(Aleurothrixus floccosus)、二點小綠葉蟬(Amrasca biguttula biguttula)、紅圓蚧(Aonidiella aurantii)、棉蚜(Aphis gossypii)、大豆蚜(Aphis glycines)、蘋果蚜(Aphis pomi)、馬鈴薯長鬚蚜(Aulacorthum solani)、銀葉粉虱(Bemisia argentifolii)、甘薯粉虱(Bemisia tabaci)、美洲穀長蝽(Blissus leucopterus)、天門冬小管蚜(Brachycorynella asparagi)、稻粉介殼蟲(Brevennia rehi)、甘藍蚜(Brevicoryne brassicae)、馬鈴薯俊盲蝽(Calocoris norvegicus)、紅蠟蚧(Ceroplastes rubens)、熱帶臭蟲(Cimex hemipterus)、溫帶臭蟲(Cimex lectularius)、Dagbertus fasciatus、Dichelops furcatus、麥雙尾蚜(Diuraphis noxia)、柑橘木虱(Diaphorina citri)、車前圓尾蚜(Dysaphis plantaginea)、美棉紅蝽(Dysdercus suturellus)、Edessa meditabunda、蘋果綿蚜(Eriosoma lanigerum)、歐扁盾蝽(Eurygaster maura)、大豆褐蝽(Euschistus heros)、褐美洲蝽(Euschistus servus)、安氏角盲蝽(Helopeltis antonii)、茶角盲蝽(Helopeltis theivora)、吹棉蚧(Icerya purchasi)、芒果黃線葉蟬(Idioscopus nitidulus)、灰飛虱(Laodelphax striatellus)、大稻緣蝽(Leptocorisa oratorius)、異稻緣蝽(Leptocorisa varicornis)、豆莢草盲蝽(Lygus hesperus)、木槿曼粉蚧(Maconellicoccus hirsutus)、大戟長管蚜(Macrosiphum euphorbiae)、麥長管蚜(Macrosiphum granarium)、薔薇長管蚜(Macrosiphum rosae)、翠菊葉蟬(Macrosteles quadrilineatus)、沫蟬(Mahanarva frimbiolata)、麥無網蚜(Metopolophium dirhodum)、長角蝽象(Mictis longicornis)、桃蚜(Myzus persicae)、黑尾葉蟬(Nephotettix cinctipes)、Neurocolpus longirostris、稻綠蝽(Nezara viridula)、褐飛虱(Nilaparvata lugens)、糠片盾蚧(Parlatoria pergandii)、黑片盾蚧(Parlatoria ziziphi)、玉米花翅飛虱(Peregrinus maidis)、葡萄根瘤蚜(Phylloxera vitifoliae)、去杉球蚧(Physokermes piceae)、加州盲蝽(Phytocoris californicus)、植盲蝽(Phytocoris relativus)、紅肩綠蝽(Piezodorus guildinii)、四線盲蝽(Poecilocapsus lineatus)、Psallus vaccinicola、Pseudacysta perseae、菠蘿潔粉蚧(Pseudococcus brevipes)、梨園盾蚧(Quadraspidiotus perniciosus)、玉米蚜(Rhopalosiphum maidis)、禾穀縊管蚜(Rhopalosiphum padi)、欖珠蠟蚧(Saissetia oleae)、Scaptocoris castanea、蚜麥二叉蚜(Schizaphis graminum)、麥長管蚜(Sitobion avenae)、白背飛虱(Sogatella furcifera)、溫室粉虱(Trialeurodes vaporariorum)、結翅粉虱(Trialeurodes abutiloneus)、矢尖蚧(Unaspis yanonensis)及Zulia entrerriana。
在另一實施例中,式I分子可用於控制膜翅目(Order Hymenoptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)切葉蟻屬(Acromyrmex spp.)、葉蟻屬(Atta spp.)、黑蟻屬(Camponotus spp.)、松葉蜂屬(Diprion spp.)、蟻屬(Formica spp.)、廚蟻屬(Monomorium spp.)、新松葉蜂屬(Neodiprion spp.)、收穫蟻屬(Pogonomyrmex spp.)、馬蜂屬
(Polistes spp.)、火蟻屬(Solenopsis spp.)、黃胡蜂屬(Vespula spp.)及木蜂屬(Xylocopa spp.)。特定物種之非窮舉性清單包括(但不限於)新疆菜葉蜂(Athalia rosae)、德克塞斯切葉蟻(Atta texana)、阿根廷蟻(Iridomyrmex humilis)、小黑蟻(Monomorium minimum)、廚蟻(Monomorium pharaonis)、紅火蟻(Solenopsis invicta)、熱帶火蟻(Solenopsis geminata)、偷竊蟻(Solenopsis molesta)、黑火蟻(Solenopsis richtery)、南方火蟻(Solenopsis xyloni)及臭家蟻(Tapinoma sessile)。
在另一實施例中,式I分子可用於控制等翅目(Order Isoptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)乳白蟻屬(Coptotermes spp.)、角白蟻屬(Cornitermes spp.)、砂白蟻屬(Cryptotermes spp.)、異白蟻屬(Heterotermes spp.)、木白蟻屬(Kalotermes spp.)、楹白蟻屬(Incisitermes spp.)、大白蟻屬(Macrotermes spp.)、緣木白蟻屬(Marginitermes spp.)、鋸白蟻屬(Microcerotermes spp.)、原角白蟻屬(Procornitermes spp.)、散白蟻屬(Reticulitermes spp.)、長鼻白蟻屬(Schedorhinotermes spp.)及古白蟻屬(Zootermopsis spp.)。特定物種之非窮舉性清單包括(但不限於)曲顎白蟻(Coptotermes curvignathus)、新西蘭乳白蟻(Coptotermes frenchii)、臺灣乳白蟻(Coptotermes formosanus)、金黃異白蟻(Heterotermes aureus)、稻麥小白蟻(Microtermes obesi)、散白蟻(Reticulitermes banyulensis)、格氏散白蟻(Reticulitermes grassei)、黃肢散白蟻(Reticulitermes flavipes)、美小黃散白蟻(Reticulitermes hageni)、西方散白蟻(Reticulitermes hesperus)、桑特散白蟻(Reticulitermes santonensis)、棲北散白蟻(Reticulitermes speratus)、美黑脛散白蟻(Reticulitermes tibialis)及美小黑散白蟻(Reticulitermes virginicus)。
在另一實施例中,式I分子可用於控制鱗翅目(Order Lepidoptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)蛾屬(Adoxophyes spp.)、夜盜蟲屬(Agrotis spp.)、卷蛾屬(Argyrotaenia spp.)、卷葉蛾屬(Cacoecia spp.)、細蛾屬(Caloptilia spp.)、禾草螟屬(Chilo spp.)、夜蛾屬(Chrysodeixis spp.)、豆粉蝶屬(Colias spp.)、草螟屬(Crambus spp.)、絹野螟屬(Diaphania spp.)、螟屬(Diatraea spp.)、金剛鑽屬(Earias spp.)、粉斑螟屬(Ephestia spp.)、尺蠖蛾屬(Epimecis spp.)、斑點夜蛾屬(Feltia spp.)、角劍夜蛾屬(Gortyna spp.)、青蟲屬(Helicoverpa spp.)、實夜蛾屬(Heliothis spp.)、Indarbela spp.、潛夜細蛾屬(Lithocolletis spp.)、切根蟲屬(Loxagrotis spp.)、天幕毛蟲屬(Malacosoma spp.)、疆夜蛾屬(Peridroma spp.)、細蛾屬(Phyllonorycter spp.)、黏夜蛾屬(Pseudaletia spp.)、蛀莖夜蛾屬(Sesamia spp.)、灰翅夜蛾屬(Spodoptera spp.)、興透翅蛾屬(Synanthedon spp.)及巢蛾屬(Yponomeuta spp.)。特定物種之非窮舉性清單包括(但不限於)飛揚阿夜蛾(Achaea janata)、棉褐帶卷蛾(Adoxophyes orana)、小地蠶(Agrotis ipsilon)、棉葉波紋夜蛾(Alabama argillacea)、鱷梨卷葉蟲(Amorbia cuneana)、臍橙螟(Amyelois transitella)、棕灰蛾
(Anacamptodes defectaria)、桃枝麥蛾(Anarsia lineatella)、黃麻橋夜蛾(Anomis sabulifera)、梨豆夜蛾(Anticarsia gemmatalis)、果樹卷葉蛾(Archips argyrospila)、玫瑰卷葉蛾(Archips rosana)、桔帶卷蛾(Argyrotaenia citrana)、伽馬叉紋夜蛾(Autographa gamma)、卷葉蛾(Bonagota cranaodes)、秈弄蝶(Borbo cinnara)、棉潛蛾(Bucculatrix thurberiella)、桔橘卷蛾(Capua reticulana)、桃蛀果蛾(Carposina niponensis)、芒果橫線尾夜蛾(Chlumetia transversa)、玫瑰色卷蛾(Choristoneura rosaceana)、稻縱卷葉螟(Cnaphalocrocis medinalis)、荔枝細蛾(Conopomorpha cramerella)、芳香木蠹蛾(Cossus cossus)、石核桃卷蛾(Cydia caryana)、李小食心蟲(Cydia funebrana)、梨小食心蟲(Cydia molesta)、豌豆小卷蛾(Cydia nigricana)、蘋果小卷蛾(Cydia pomonella)、茶刺蛾(Darna diducta)、小蔗螟(Diatraea saccharalis)、西南玉米桿草螟(Diatraea graniosella)、埃及金剛鑽(Earias insulata)、翠紋金剛鑽(Earias vitella)、對小卷蛾(Ecdytolopha aurantianum)、南美玉米苗斑螟(Elasmopalpus lignosellus)、粉斑螟(Ephestia cautella)、菸草粉斑螟(Ephestia elutella)、地中海粉螟(Ephestia kuehniella)、夜小卷蛾(Epinotia aporema)、淡棕蘋果蛾(Epiphyas postvittana)、香蕉弄蝶(Erionota thrax)、女貞細卷蛾(Eupoecilia ambiguella)、根切原蟲(Euxoa auxiliaris)、東方蛀果蛾(Grapholita molesta)、三紋螟蛾(Hedylepta indicata)、棉鈴蟲(Helicoverpa armigera)、穀實夜蛾
(Helicoverpa zea)、菸芽夜蛾(Heliothis virescens)、菜心野螟(Hellula undalis)、番茄蠹蛾(Keiferia lycopersicella)、茄白翅野螟(Leucinodes orbonalis)、咖啡潛葉蛾(Perileucoptera coffeella)、旋紋潛蛾(Leucoptera malifoliella)、葡萄小卷葉蛾(Lobesia botrana)、豆白綠切根蟲(Loxagrotis albicosta)、舞毒蛾(Lymantria dispar)、桃潛蛾(Lyonetia clerkella)、蓑蛾(Mahasena corbetti)、甘藍夜蛾(Mamestra brassicae)、豆莢野螟(Maruca testulalis)、袋蛾(Metisa plana)、栗夜盜蟲(Mythimna unipuncta)、番茄蛀蟲(Neoleucinodes elegantalis)、三點水螟(Nymphula depunctalis)、秋尺蛾(Operophtera brumata)、玉米螟(Ostrinia nubilalis)、Oxydia vesulia、疆褐卷蛾(Pandemis cerasana)、蘋褐卷蛾(Pandemis heparana)、非洲達摩鳳蝶(Papilio demodocus)、紅鈴麥蛾(Pectinophora gossypiella)、雜色地老虎(Peridroma saucia)、咖啡潛葉蛾(Perileucoptera coffeella)、馬鈴薯塊莖蛾(Phthorimaea operculella)、柑橘葉潛蛾(Phyllocnisitis citrella)、菜粉蝶(Pieris rapae)、苜蓿綠夜蛾(Plathypena scabra)、印度穀斑蛾(Plodia interpunctella)、菜蛾(Plutella xylostella)、卷蛾(Polychrosis viteana)、桔果巢蛾(Prays endocarpa)、油橄欖巢蛾(Prays oleae)、一星黏蟲(Pseudaletia unipuncta)、大豆夜蛾(Pseudoplusia includens)、尺蠖(Rachiplusia nu)、三化螟(Scirpophaga incertulas)、稻蛀莖夜蛾(Sesamia inferens)、粉莖螟(Sesamia nonagrioides)、銅斑褐刺蛾(Setora nitens)、
麥蛾(Sitotroga cerealella)、葡萄長鬚卷蛾(Sparganothis pilleriana)、甜菜夜蛾(Spodoptera exigua)、草地貪夜蛾(Spodoptera fugiperda)、南部灰翅夜蛾(Spodoptera eridania)、菠蘿褐灰蝶(Thecla basilides)、衣蛾(Tineola bisselliella)、粉斑夜蛾(Trichoplusia ni)、番茄斑潛蠅(Tuta absoluta)、咖啡豹蠹蛾(Zeuzera coffeae)及梨豹蠹蛾(Zeuzera pyrina)。
在另一實施例中,式I分子可用於控制食毛目(Order Mallophaga)之害蟲。特定屬之非窮舉性清單包括(但不限於)細鵝虱屬(Anaticola spp.)、牛毛虱屬(Bovicola spp.)、大火雞虱屬(Chelopistes spp.)、雞角羽虱(Goniodes spp.)、雞虱屬(Menacanthus spp.)及犬食毛屬(Trichodectes spp.)。特定物種之非窮舉性清單包括(但不限於)牛羽虱(Bovicola bovis)、山羊住牛虱(Bovicola caprae)、綿羊虱(Bovicola ovis)、大火雞虱(Chelopistes meleagridis)、雞角羽虱(Goniodes dissimilis)、大角羽虱(Goniodes gigas)、火雞短角鳥虱(Menacanthus stramineus)、雞羽虱(Menopon gallinea)及犬嚙毛虱(Trichodectes canis)。
在另一實施例中,式I分子可用於控制直翅目(Order Orthoptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)蚱蜢屬(Melanoplus spp.)及側羽葉屬(Pterophylla spp.)。特定物種之非窮舉性清單包括(但不限於)黑斑阿納螽(Anabrus simplex)、非洲螻蛄(Gryllotalpa africana)、南方螻蛄(Gryllotalpa australis)、黑短螻蛄(Gryllotalpa brachyptera)、螻蛄(Gryllotalpa hexadactyla)、東亞飛蝗(Locusta migratoria)、綱翅細刺螽(Microcentrum retinerve)、沙漠蝗(Schistocerca gregaria)及叉尾斯奎螽(Scudderia furcata)。
在另一實施例中,式I分子可用於控制蚤目(Order Siphonaptera)之害蟲。特定物種之非窮舉性清單包括(但不限於)雞蚤(Ceratophyllus gallinae)、雞角葉蚤(Ceratophyllus niger)、犬櫛頭蚤(Ctenocephalides canis)、貓櫛頭蚤(Ctenocephalides felis)及人蚤(Pulex irritans)。
在另一實施例中,式I分子可用於控制纓翅目(Order Thysanoptera)之害蟲。特定屬之非窮舉性清單包括(但不限於)巢針薊馬屬(Caliothrips spp.)、花薊馬屬(Frankliniella spp.)、硬薊馬屬(Scirtothrips spp.)及薊馬屬(Thrips spp.)。特定物種之非窮舉性清單包括(但不限於)菸褐薊馬(Frankliniella fusca)、西花薊馬(Frankliniella occidentalis)、梳缺花薊馬(Frankliniella schultzei)、威廉期花薊馬(Frankliniella williamsi)、溫室薊馬(Heliothrips haemorrhaidalis)、腹鉤薊馬(Rhipiphorothrips cruentatus)、桔硬薊馬(Scirtothrips citri)、茶黃薊馬(Scirtothrips dorsalis)及薊馬(Taeniothrips rhopalantennalis)、黃胸薊馬(Thrips hawaiiensis)、豆黃薊馬(Thrips nigropilosus)、東方薊馬(Thrips orientalis)、菸薊馬(Thrips tabaci)。
在另一實施例中,式I分子可用於控制纓尾目(Order Thysanura)之害蟲。特定屬之非窮舉性清單包括(但
不限於)衣魚屬(Lepisma spp.)及衣角屬(Thermobia spp.)。
在另一實施例中,式I分子可用於控制蜱蟎目(Order Acarina)之害蟲。特定屬之非窮舉性清單包括(但不限於)粉蟎屬(Acarus spp.)、刺皮癭蟎屬(Aculops spp.)、牛蜱屬(Boophilus spp.)、脂蟎屬(Demodex spp.)、革蜱屬(Dermacentor spp.)、上癭蟎屬(Epitimerus spp.)、癭蟎屬(Eriophyes spp.)、硬蜱屬(Ixodes spp.)、小爪蟎屬(Oligonychus spp.)、全爪蟎屬(Panonychus spp.)、根蟎屬(Rhizoglyphus spp.)及葉蟎屬(Tetranychus spp.)。特定物種之非窮舉性清單包括(但不限於)氏蜂跗腺蟎(Acarapis woodi)、粗腳粉蟎(Acarus siro)、瘤癭蟎(Aceria mangiferae)、番茄刺皮癭蟎(Aculops lycopersici)、皮氏刺皮癭蟎(Aculus pelekassi)、斯氏刺癭蟎(Aculus schlechtendali)、美洲鈍眼蜱(Amblyomma americanum)、卵形短鬚蟎(Brevipalpus obovatus)、紫紅短鬚蟎(Brevipalpus phoenicis)、美洲狗蜱(Dermacentor variabilis)、屋塵蟎(Dermatophagoides pteronyssinus)、鵝耳櫪始葉蟎(Eotetranychus carpini)、貓耳蟎(Notoedres cati)、咖啡小爪蟎(Oligonychus coffee)、冬青小爪蟎(Oligonychus ilicus)、柑橘全爪蟎(Panonychus citri)、蘋果全爪蟎(Panonychus ulmi)、桔皺葉刺癭蟎(Phyllocoptruta oleivora)、食跗線蟎屬(Polyphagotarsonemun latus)、血紅扇頭蜱(Rhipicephalus sanguineus)、疥蟎(Sarcoptes scabiei)、鱷梨頂冠癭蟎(Tegolophus perseaflorae)、二點葉蟎(Tetranychus urticae)
及狄氏瓦蟎(Varroa destructor)。
在另一實施例中,式I分子可用於控制綜合目(Order Symphyla)之害蟲。特定物種之非窮舉性清單包括(但不限於)白松蟲(Scutigerella immaculata)。
在另一實施例中,式I分子可用於控制線蟲動物門(Phylum Nematoda)之害蟲。特定屬之非窮舉性清單包括(但不限於)線蟲屬(Aphelenchoides spp.)、刺線蟲屬(Belonolaimus spp.)、小環線蟲屬(Criconemella spp.)、莖線蟲屬(Ditylenchus spp.)、棘皮線蟲屬(Heterodera spp.)、潛根線蟲屬(Hirschmanniella spp.)、紐帶線蟲屬(Hoplolaimus spp.)、根結線蟲屬(Meloidogyne spp.)、短體線蟲屬(Pratylenchus spp.)及穿孔線蟲屬(Radopholus spp.)。特定物種之非窮舉性清單包括(但不限於)犬惡絲蟲(Dirofilaria immitis)、玉米胞囊線蟲(Heterodera zeae)、南方根結線蟲(Meloidogyne incognita)、爪哇根瘤線蟲(Meloidogyne javanica)、旋盤尾絲蟲(Onchocerca volvulus)、相似穿孔線蟲(Radopholus similis)及香蕉腎狀線蟲(Rotylenchus reniformis)。
關於其他資訊,查閱「HANDBOOK OF PEST CONTROL-THE BEHAVIOR,LIFE HISTORY,AND CONTROL OF HOUSEHOLD PESTS」Arnold Mallis,第9版,GIE Media Inc 2004版權所有。
施用
式I分子通常以每公頃約0.01公克至每公頃約
5000公克之量使用以提供控制。通常較佳為每公頃約0.1公克至每公頃約500公克之量,且通常更佳為每公頃約1公克至每公頃約50公克之量。
式I分子施用之區域可為害蟲居住(或可能居住或經過)之任何區域,例如:作物、樹木、水果、穀類、飼料物種、藤本植物、草皮及觀賞植物生長處;家養動物居住處;建築物之內部或外部表面(諸如穀物儲存之位置)、建築物中使用之建築材料(諸如浸漬木材)及建築物周圍之土壤。使用式I分子之特定作物區域包括生長以下各者或將種植以下各者之種子的區域:蘋果、玉米、向日葵、棉花、大豆、芥花、小麥、稻米、高粱、大麥、燕麥、馬鈴薯、橙子、苜蓿、萵苣、草莓、番茄、胡椒、十字花科植物、梨、菸草、杏仁、甜菜、豆子及其他有價值作物。亦有利的為在各種植物生長時使用硫酸銨與式I分子。
控制害蟲通常意謂害蟲群體、害蟲活動性或兩者在區域內降低。此可在如下情況時發生:害蟲群體自區域逐退;害蟲在區域內或在區域周圍無能力;或害蟲整體或部分在區域內或在區域周圍滅絕。當然,可發生此等結果之組合。一般而言,害蟲群體、活動性或兩者所需地降低超過50%,較佳超過90%。一般而言,區域不在人類之中或之上;因此,位置通常為非人類區域。
式I分子可以混合物的形式使用,同時或依序施用、單獨或與其他增強植物活力(例如長出更好的根系、更好地經受脅迫生長條件)之化合物一起施用。該等其他化合
物為例如調節植物乙烯受體之化合物,最值得注意的為1-甲基環丙烯(亦稱為1-MCP)。另外,該等分子可在害蟲活動性較低期間使用,諸如在生長中之植物開始製造有價值之農產品之前。該等時間包括害蟲壓力通常較低時之早播季。
式I分子可施用至植物之葉子及果實部分以控制害蟲。該等分子將直接與害蟲接觸,或害蟲在食用含有殺蟲劑之葉子、果實或浸出汁液時消耗該等殺蟲劑。式I分子亦可施用至土壤且當以此方式施用時,食用根及莖之害蟲可得以控制。根可吸收分子,將其吸取至植物之葉子部分以控制在地面上咀嚼及食用汁液之害蟲。
一般而言,在誘餌情況下,將誘餌置於例如白蟻可與誘餌接觸及/或受其吸引之地面。亦可將誘餌施用至例如螞蟻、白蟻、蟑螂及蒼蠅可與誘餌接觸及/或受其吸引之建築物表面(水平、垂直或傾斜表面)。誘餌可包含式I分子。
式I分子可囊封在膠囊內、或置放於膠囊表面上。膠囊大小可在奈米大小(直徑約100-900奈米)至微米大小(直徑約10-900微米)範圍內。
由於一些害蟲之卵具有抗某些殺蟲劑之獨特能力,故可能需要重複施用式I分子以控制新出現之幼蟲。
殺蟲劑在植物中之系統移動可用於藉由將式I分子施用(例如藉由噴灑區域)至植物之不同部位而對植物之一個部位進行害蟲控制。舉例而言,例如,食葉昆蟲之控制可藉由滴灌或條施,藉由以例如種植前或種植後之土壤澆灌而處理土壤,或藉由種植前處理植物種子來達成。
種子處理可應用於所有類型之種子,包括經遺傳修飾以表現特殊特性之植物將發芽者。代表性實例包括對無脊椎動物害蟲(諸如蘇力菌)表現蛋白毒性或其他殺昆蟲毒素者,表現除草劑抗性者,諸如「Roundup Ready」種子,或具有表現殺昆蟲毒素、除草劑抗性、營養增強、抗旱性或任何其他有益特性之「堆疊式」外來基因者。另外,該等使用式I分子之種子處理可進一步增強植物較好地經受住脅迫生長條件之能力。由此產生較健康,較有活力之植物,此可引起在收割期時之較高產量。一般而言,每100,000個種子約1公克式I分子至約500公克預期提供良好益處,每100,000個種子約10公克至約100公克之量預期提供更佳益處,且每100,000個種子約25公克至約75公克之量預期提供甚至更佳益處。
應容易地顯而易知,式I分子可用於以下植物之上、之中或周圍:經遺傳修飾以表現特殊特性(諸如蘇力菌或其他殺昆蟲毒素)之植物,或表現除草劑抗性之植物,或具有表現殺昆蟲毒素、除草劑抗性、營養增強或任何其他有益特性之「堆疊式」外來基因之植物。
式I分子可用於控制獸醫學領域或在非人類動物飼養領域中之內寄生蟲及外寄生蟲。式I分子諸如藉由以例如錠劑、膠囊、飲料、顆粒形式經口投與,藉由以例如浸泡、噴灑、傾倒、點藥及噴粉形式塗覆皮膚,及藉由以例如注射劑形式非經腸投與來施用。
式I分子亦可有利地用於家蓄飼養,例如牛、羊、
豬、雞及鵝。其亦可有利地用於寵物,諸如馬、犬及貓。欲控制之特定害蟲將為會對該等動物造成麻煩之跳蚤及蜱。適合之調配物與飲用水或飼料一起經口投與該等動物。適合之劑量及調配物視物種而定。
式I分子亦可用於控制上列動物中之寄生蟲,尤其腸內寄生蟲。
式I分子亦可用於人類健康照護之治療方法。該等方法包括(但不限於)以例如錠劑、膠囊、飲料、顆粒形式經口投與及藉由皮膚塗覆。
全世界之害蟲正遷移至新環境(對於該害蟲而言),且此後在該新環境中變成新的侵入物種。式I分子亦可用於該等新的侵入物種以在該新環境中對其進行控制。
式I分子亦可用於植物(諸如作物)生長(例如種植前、種植中、收穫前)之區域,及存在會對該等植物造成商業上損害之較低程度(甚至無實際存在)害蟲之區域。在該區域中使用該等分子會使在該區域中生長之植物受益。該等益處可包括(但不限於)改進植物健康,改進植物產量(例如增加生物質及/或增加有價值成分之含量),改進植物活力(例如改進植物生長及/或更綠之葉子),改進植物品質(例如改進某些成分之含量或組成),及改進植物對非生物及/或生物脅迫之耐受性。
在殺蟲劑可被使用或商業銷售之前,該殺蟲劑經歷各種政府機構(地方、區域、州、國家及國際)之長時間之評估過程。大量資料要求由管理當局來規定且必須由產品
註冊者或代表產品註冊者之第三方經由資料生成及提交(通常使用與全球資訊網連接之電腦)來處理。接著,此等政府機構審閱該資料,且若作出安全性決定,則提供可能使用者或販售者以產品註冊許可。此後,在產品註冊被授予及支持之地方,該使用者或販售者可使用或販售該殺蟲劑。
根據式I之分子可經測試以測定其對抗害蟲之功效。另外,可進行作用模式研究以測定該分子是否具有與其他殺蟲劑相比不同的作用模式。此後,此獲得之資料可藉由諸如網際網路傳播至第三方。
此文件中之標題僅為了方便且不能用於解釋其任何部分。
表格部分
Claims (5)
- 一種組成物,其包含根據式I之分子:
- 如請求項1之分子,其中該分子具有下列結構
- 如請求項1之分子,其具有下列結構之一者:
- 如請求項1之組成物,其進一步包含:(a)一或多種具有殺蟎、殺藻、殺卵、殺細菌、殺真菌、除草、殺昆蟲、殺軟體動物、殺線蟲、殺嚙齒類動物或殺病毒性質之化合物;或(b)一或多種化合物,其作為拒食劑、驅鳥劑、化 學絕育劑、除草劑安全劑、誘蟲劑、驅蟲劑、驅哺乳動物劑、交配干擾劑、植物活化劑、植物生長調節劑或增效劑;或(c)(a)及(b)兩者。
- 一種方法,其包含將呈一足以控制害蟲之量的如請求項1之組成物施用至一區域以控制該害蟲。
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