TWI669292B - 經由酮亞胺醯化製備３，５－雙（鹵烷基）吡唑之方法 - Google Patents
經由酮亞胺醯化製備３，５－雙（鹵烷基）吡唑之方法 Download PDFInfo
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- TWI669292B TWI669292B TW104118560A TW104118560A TWI669292B TW I669292 B TWI669292 B TW I669292B TW 104118560 A TW104118560 A TW 104118560A TW 104118560 A TW104118560 A TW 104118560A TW I669292 B TWI669292 B TW I669292B
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- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 150000003217 pyrazoles Chemical class 0.000 title abstract description 5
- 150000004658 ketimines Chemical class 0.000 title abstract description 4
- 230000010933 acylation Effects 0.000 title abstract 2
- 238000005917 acylation reaction Methods 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 8
- -1 2-difluoroethyl Chemical group 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000004781 2,2-dichloro-2-fluoroethyl group Chemical group [H]C([H])(*)C(F)(Cl)Cl 0.000 claims description 3
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 3
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 claims description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 claims description 3
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 claims description 3
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 claims description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000006337 tetrafluoro ethyl group Chemical group 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 12
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229940073584 methylene chloride Drugs 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 150000003456 sulfonamides Chemical class 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- NICRTVVFOCBIKC-UHFFFAOYSA-N CC(C)N=C(C)C(F)F Chemical compound CC(C)N=C(C)C(F)F NICRTVVFOCBIKC-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 229940117389 dichlorobenzene Drugs 0.000 description 3
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XHILZHAQBOLGFD-UHFFFAOYSA-N 1,1-difluoropropan-2-one Chemical compound CC(=O)C(F)F XHILZHAQBOLGFD-UHFFFAOYSA-N 0.000 description 2
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical class OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 2
- YYPFZXBEOCAFDL-UHFFFAOYSA-N 3,5-bis(difluoromethyl)-1h-pyrazole Chemical compound FC(F)C=1C=C(C(F)F)NN=1 YYPFZXBEOCAFDL-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002429 hydrazines Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- MYVITOFBNPFGNU-UHFFFAOYSA-N n-benzyl-1,1,1-trifluoropropan-2-imine Chemical compound FC(F)(F)C(C)=NCC1=CC=CC=C1 MYVITOFBNPFGNU-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- IYXUFOCLMOXQSL-UHFFFAOYSA-N (2,2-difluoroacetyl) 2,2-difluoroacetate Chemical compound FC(F)C(=O)OC(=O)C(F)F IYXUFOCLMOXQSL-UHFFFAOYSA-N 0.000 description 1
- 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 1
- YTBBOHJDGLEWEF-UHFFFAOYSA-N 1,1,1-trifluoro-n-propan-2-ylpropan-2-imine Chemical compound CC(C)N=C(C)C(F)(F)F YTBBOHJDGLEWEF-UHFFFAOYSA-N 0.000 description 1
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 1
- 125000004515 1,2,4-thiadiazol-3-yl group Chemical group S1N=C(N=C1)* 0.000 description 1
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 1
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- DTJIBVSGNIAPCX-UHFFFAOYSA-N 2,2,2-trifluoroacetyl bromide Chemical compound FC(F)(F)C(Br)=O DTJIBVSGNIAPCX-UHFFFAOYSA-N 0.000 description 1
- DCEPGADSNJKOJK-UHFFFAOYSA-N 2,2,2-trifluoroacetyl fluoride Chemical compound FC(=O)C(F)(F)F DCEPGADSNJKOJK-UHFFFAOYSA-N 0.000 description 1
- KURKJXZWCPWPFX-UHFFFAOYSA-N 2,2-difluoroacetyl chloride Chemical compound FC(F)C(Cl)=O KURKJXZWCPWPFX-UHFFFAOYSA-N 0.000 description 1
- CRLSHTZUJTXOEL-UHFFFAOYSA-N 2,2-difluoroacetyl fluoride Chemical compound FC(F)C(F)=O CRLSHTZUJTXOEL-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000004780 2-chloro-2,2-difluoroethyl group Chemical group [H]C([H])(*)C(F)(F)Cl 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZPQNVNQWYSTELD-UHFFFAOYSA-N 4,4,4-trifluoro-3-oxobutanoyl chloride Chemical compound FC(F)(F)C(=O)CC(Cl)=O ZPQNVNQWYSTELD-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- JNZMCMSGSKHZQW-UHFFFAOYSA-N 5-(difluoromethyl)-3-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)C1=CC(C(F)(F)F)=NN1 JNZMCMSGSKHZQW-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- AJZKCZBXGUUREN-UHFFFAOYSA-N N-benzyl-1,1-difluoropropan-2-imine Chemical compound FC(C(C)=NCC1=CC=CC=C1)F AJZKCZBXGUUREN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
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- 238000001311 chemical methods and process Methods 0.000 description 1
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Abstract
本發明係關於經由酮亞胺醯化製備3,5-雙(鹵烷基)吡唑衍生物之新穎方法。
Description
本發明係關於製備3,5-雙(鹵烷基)吡唑衍生物之新穎方法。
多氟烷基吡唑基羧酸衍生物及3,5-雙(鹵烷基)吡唑為殺真菌活性組成份之有價值的先驅物(WO 2003/070705，WO 2008/013925，WO 2012/025557)。
吡唑羧酸衍生物典型的係藉由將具有兩個釋離基團之丙烯酸衍生物與肼類進行反應而製備(WO 2009/112157及WO 2009/106230)。WO 2005/042468係揭示藉由將醯基鹵與二烷基胺基丙烯酸酯進行反應且隨即將其等用烷基肼予以環化而製備2-二鹵醯基-3-胺基丙烯酸酯之方法。WO 2008/022777係說明藉由將α,α-二氟胺於路易斯酸存在之下與丙烯酸衍生物進行反應，且隨即將其等與烷基肼進行反應而製備3-二鹵甲基吡唑-4-羧酸衍生物的方法。
3,5-雙(氟烷基)吡唑係藉由將雙全氟烷基二酮(如1,1,1,5,5,5-六氟乙醯丙酮)與肼類進行反應而製備(參見Pashkevich等，Zhurnal Vsesoyuznogo Khimicheskogo Obshchestva im.D.I.Mendeleeva(1981)，26(1)，105-7)，該產率僅為27-40%。該多氟烷基二酮之合成，單離及純化係非常複雜，因為該化合物通常極易揮發且為劇毒。
鑑於上述已知技藝，本發明之目的在於提供一製法，其不具有上述缺點且因此以高產率途徑得到3,5-雙(鹵烷基)吡唑衍生物。
上述目的可藉由製備式(Ia)及(Ib)3,5-雙(鹵烷基)吡唑之方法而達成，
其中，R1及R3 係各自獨立選自C1-C6-鹵烷基；R2 係選自H，鹵素，COOH，(C=O)OR5，CN及(C=O)NR6R7；R4 係選自H，C1-C8-烷基，芳基，吡啶基；R5 係選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基及C7-19-烷基芳基；R6及R7 係各自獨立選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基及C7-19-烷基芳基，或其中，R6及R7 與其等所鍵接之氮原子一起可形成一四-，五-或六員環，其特徵在於：於步驟(A)，將式(II)酸衍生物，
其中，R1 係定義如前，X 為F，Cl，Br或-OC(O)R1，與式(III)化合物進行反應
其中，R8 係選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基及C7-19-烷基芳基，OR9；R9 係選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基，C7-19-烷基芳基；R2及R3 係定義如前；而形成式(IV)化合物
其中，R1，R2，R3，R5，R6，R7，R8，R9係定義如前，及於步驟(B)，將(IV)於(V)NH2NHR4存在之下予以環化，其中，R4係定義如前，形成了(Ia)及(Ib)。
根據本發明之較佳製法為，其中，於式(Ia)，(Ib)，(II)，(III)，(IV)及(V)中之基團係定義如下：R1及R3 係各自獨立選自二氟甲基，三氟甲基，氯氟甲基，二氯氟甲基，氯二氟甲基，1-氟乙基，2-氟乙基，2,2-二氟乙基，2,2,2-三氟乙基，2-氯-2-氟乙基，2-二氟乙基，2,2-二氯-2-氟乙基，2,2,2-三氯乙基，四氟乙基(CF3CFH)，五氟乙基及1,1,1-三氟丙-2-基；R2 係選自H，F，Cl，Br，COOCH3，COOC2H5，COOC3H7，CN及CON(CH3)2，CON(C2H5)2；R4 係選自H，C1-C8烷基，芳基，吡啶基；
R8 係各自獨立選自甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，環丙基，環丁基，環戊基，環己基，苯基，苄基，苯基乙基，甲苯基，2,3-，2,4-，2,5-，2,6-，3,4-或3,5-二甲基苯基；X 係選自F，Cl或-O(CO)R1。
根據本發明之更佳製法為，其中，於式(Ia)，(Ib)，(II)，(III)，(IV)及(V)中之基團係定義如下：R1及R3 係各自獨立選自三氟甲基，二氟甲基，二氟氯甲基，五氟乙基；R2 係選自H，Cl，CN，COO(C2H5)2；R4 係選自H，甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，正戊基，正己基，1,3-二甲基丁基，3,3-二甲基丁基，芳基；R8 係選自甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，環丙基，環丁基，環戊基，環己基，苄基；X 係選自F，Cl或-OC(O)R1。
根據本發明之更為佳之製法為，其中，於式(Ia)，(Ib)，(II)，(III)，(IV)及(V)中之基團係定義如下：R1及R3 係各自獨立選自CF2H，CF3；R2 係選自H或COOC2H5；R4 係選自H，甲基，乙基，苯基；R8 係選自乙基，正-，異丙基，正-，環戊基，環己基，苄基；X 為Cl或F。
根據本發明之最佳製法為，其中，於式(Ia)，(Ib)，(II)，(III)，(IV)及(V)中之基團係定義如下：R1及R3 係各自獨立選自CF2H，CF3；R2 為H；R4 係選自H，甲基，苯基；R8 係選自異丙基，苄基；X 為Cl或F。
令人驚奇的，該式(I)吡唑可在本發明條件下以良好產率及高純
度製得，此意味根據本發明之製法克服了先前於已知技藝中說明之製備方法中的上述缺點。
於本發明內文中，”鹵素”(Hal)，除非有不同定義，係包括選自含有氟，氯，溴及碘，宜為氟，氯及溴，更宜為氟及氯之元素。
任意經取代之基團可為單-或多取代，當為多取代之情況時，該取代基可相同或不同。
鹵烷基：具有1至6個且宜為1至3個碳原子(如上特定)之直鏈或分支烷基，其中，於這些基團中之一些或所有的氫原子可如上特定被鹵素原子所代替，例如(但非侷限於)C1-C3-鹵烷基，如氯甲基，溴甲基，二氯甲基，三氯甲基，氟甲基，二氟甲基，三氟甲基，氯氟甲基，二氯氟甲基，氯二氟甲基，1-氯乙基，1-溴乙基，1-氟乙基，2-氟乙基，2,2-二氟乙基，2,2,2-三氟乙基，2-氯-2-氟乙基，2-氯-2,2-二氟乙基，2,2-二氯-2-氟乙基，2,2,2-三氯乙基，五氟乙基及1,1,1-三氟丙-2-基。此定義亦適用於當鹵烷基作為組合式取代基之一部份時，例如鹵烷基胺基烷基等，除非另有定義。宜為被一個或多個鹵素原子所取代之烷基基團，例如三氟甲基(CF3)，二氟甲基(CHF2)，CF3CH2，CF2Cl或CF3CCl2。
烷基基團，於本發明內文中，除非有不同定義，為直鏈或分支飽和烴基基團。C1-C12-烷基之定義包括本文中烷基基團所定義之最大範圍。特別的，此定義包括之意義為，例如，甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，正戊基，正己基，1,3-二甲基丁基，3,3-二甲基丁基，正庚基，正壬基，正癸基，正十一烷基或正十二烷基。
環烷基：具有3至8個且宜為3至6個碳環員之單環飽和烴基基團，例如(但非侷限於)環丙基，環戊基及環己基。此定義亦適用於當環烷基作為組合式取代基之一部份時，例如環烷基烷基等，除非另有定義。
芳基基團，於本發明內文中，除非有不同定義，為芳族烴基基團，其可具有一個，兩個或多個選自O，N，P及S之雜原子。C6-18-芳基之定義包括本文中於具有5至18個骨架原子之芳基基團中所定義之最大範
圍，其中之碳原子可交換為雜原子。特別的，此定義包括之意義為，例如，苯基，環庚三烯基，環辛四烯，萘基及蒽基；2-呋喃基，3-呋喃基，2-噻吩基，3-噻吩基，2-吡咯基，3-吡咯基，3-異唑基，4-異唑基，5-異唑基，3-異噻唑基，4-異噻唑基，5-異噻唑基，3-吡唑基，4-吡唑基，5-吡唑基，2-唑基，4-唑基，5-唑基，2-噻唑基，4-噻唑基，5-噻唑基，2-咪唑基，4-咪唑基，1,2,4-二唑-3-基，1,2,4-二唑-5-基，1,2,4-噻二唑-3-基，1,2,4-噻二唑-5-基，1,2,4-三唑-3-基，1,3,4-二唑-2-基，1,3,4-噻二唑-2-基及1,3,4-三唑-2-基；1-吡咯基，1-吡唑基，1,2,4-三唑-1-基，1-咪唑基，1,2,3-三唑-1-基，1,3,4-三唑-1-基；3-嗒基，4-嗒基，2-嘧啶基，4-嘧啶基，5-嘧啶基，2-吡基，1,3,5-三-2-基及1,2,4-三-3-基。
芳基烷基基團(芳烷基基團)，於本發明內文中，除非不同定義，為被芳基基團所取代之烷基基團，其可具有一個C1-8-伸烷基鏈且可，於芳基骨架，具有一個或多個選自O，N，P及S之雜原子。C7-19-芳烷基基團之定義包括本文中於具有7至19個骨架原子及伸烷基鏈之芳基烷基基團中所定義之最大範圍。特別的，此定義包括之意義為，例如，苄基及苯基乙基。
烷基芳基基團(烷芳基基團)，於本發明內文中，除非不同定義，為被烷基基團所取代之芳基基團，可具有一個C1-8-伸烷基鏈且可於芳基骨架，具有一個或多個選自O，N，P及S之雜原子。C7-19-烷基芳基基團之定義包括本文中於具有7至19個骨架原子及伸烷基鏈之烷基芳基基團中所定義之最大範圍。特別的，此定義包括之意義為，例如，甲苯基或2,3-，2,4-，2,5-，2,6-，3,4-或3,5-二甲基苯基。
於本發明內文中所使用之中間體一詞係說明一物質，其出現於根據本發明之製法中且係製備以供進一步之化學製程且係於其中消耗或使用以便轉化為另一物質。該中間體通常可單離出來且立即被儲存或未經事前單離而使用於隨即之反應步驟中。"中間體"之詞亦包括通常為不穩定且短暫的中間體，其係短暫出現在多階段反應(分段反應)中且於其中可分配局部最小的反應能量分佈。
本發明化合物可以任何可能之不同異構型式之混合物存在，尤其是立體異構物，例如E及Z異構物，蘇及赤異構物，及光學異構物，但如果適當亦可為互變異構體。E及Z異構物兩者經揭示並請求專利，如蘇和赤異構物，以及光學異構物，這些異構物之任何混合物，以及可能的互變異構型式。
於步驟A中，式(II)酸衍生物係在一鹼存在之下與式(III)化合物進行反應。
較佳之式(II)化合物為三氟乙醯氯，三氟乙醯氟，二氟乙醯氟，
二氟乙醯氯，三氟乙醯溴。其亦可於原位產生式(II)化合物，例如，使用三氟醋酸，特戊醯氯及吡啶(參見WO 2003/051820)。
根據本發明之式(IV)化合物的合成反應係在0℃至+120℃之溫度時，宜在+20℃至+100℃之溫度時，更宜在20℃至+60℃之溫度時，及於標準壓力下進行。典型的鹼為：三烷基胺，吡啶，烷基吡啶，甲基吡啶，DBU。宜以吡啶作為鹼。
該反應時間並非關鍵且，根據批次份量及溫度，可在數分鐘及數小時之範圍內選擇。
於步驟A中，係將1至2mol，宜為1至1.5mol，最宜為1至1.2mol之式(II)酸衍生物與1mol式(III)化合物進行反應。
適當的溶劑為，例如，脂族，脂環族或芳族烴類，例如石油醚，正己烷，正庚烷，環己烷，甲基環己烷，苯，甲苯，二甲苯或萘烷，及鹵化烴類，例如氯苯，二氯苯，二氯甲烷，氯仿，四氯甲烷，二氯乙烷或三氯乙烷，醚類，如二乙醚，二異丙醚，甲基第三丁醚，甲基第三戊醚，二烷，四氫呋喃，1,2-二甲氧基乙烷，1,2-二乙氧基乙烷或苯甲醚；腈類，如乙腈，丙腈，正-或異丁腈或苄腈；醯胺類，如N,N-二甲基甲醯胺，N,N-二甲基乙醯胺，N-甲基甲醯苯胺，N-甲基吡咯烷酮或六甲基磷醯胺；亞碸類，如二甲亞碸或碸類，如環丁碸。特別宜為，例如，THF，乙腈類，醚類，甲苯，二甲苯，氯苯，正己烷，環己烷或甲基環己烷，且特別宜為，例如，二氯甲烷，醚或二氯甲烷。式(IV)化合物可未經事前處理而使用於環化步驟中。或者，其等可藉由適當的處理步驟而單離，特性化及任意的進一步純化。
式(III)化合物可由醛或酮及第一胺製備。該製法係於10及110℃之溫度時進行，通常不需任何溶劑，或於有機溶劑，如甲苯，二氯甲烷或醚類中。亦可使用路易斯酸，如BF3，TiCl4來加速酮亞胺的形成(亦請參見Röschentahller等，J.Fluorine.Chem.v.125，n.6，1039-1049及Tetrahedron，69(2013)，3878-3884)。
步驟B係式(IV)化合物於式(V)化合物存在之下的環化反應。
於步驟B中，1mol式(IV)化合物係使用1mol至2mol，宜為1至1.5mol式(V)肼。
於步驟B中，環化反應係在-40℃至+80℃之溫度時，宜在+20℃至+70℃之溫度時，更宜在+60℃及於標準壓力下進行。
該反應時間並非關鍵且，根據批次份量及溫度，可在相當大的範圍內選擇。
典型的，該環化反應步驟B進行時溶劑未改變。
適當的溶劑為，例如，脂族，脂環族或芳族烴類，例如石油醚，正己烷，正庚烷，環己烷，甲基環己烷，苯，甲苯，二甲苯或萘烷，及鹵化烴類，例如氯苯，二氯苯，二氯甲烷，氯仿，四氯甲烷，二氯乙烷或三氯乙烷，醚類，如二乙醚，二異丙醚，甲基第三丁醚，甲基第三戊醚，二烷，四氫呋喃，1,2-二甲氧基乙烷，1,2-二乙氧基乙烷或苯甲醚；腈類，如乙腈，丙腈，正-或異丁腈或苄腈；醯胺類，如N,N-二甲基甲醯胺，N,N-二甲基乙醯胺，N-甲基甲醯苯胺，N-甲基吡咯烷酮或六甲基磷醯胺；亞碸類，如二甲亞碸或碸類，如環丁碸，醇類，如甲醇，乙醇，異丙醇或丁醇。特別佳者為，例如，THF，乙腈，醚類，甲苯，二甲苯，氯苯，正己烷，環己烷或甲基環己烷，乙醇且最特別佳為，例如，乙腈，THF，醚，二氯甲烷，乙醇。
典型的，該式(IV)及(V)化合物之環化反應係在酸性條件下進行。
宜為無機酸，例如H2SO4，HCl，HF，HBr，HI，H3PO4或有機酸，例如CH3COOH，CF3COOH，對甲苯磺酸，甲烷磺酸，三氟甲烷磺酸。1mol式(IV)化合物係使用0.1mol至2mol，宜為0.1至1.5mol酸。
適當的溶劑為，例如，脂族，脂環族或芳族烴類，例如石油醚，正己烷，正庚烷，環己烷，甲基環己烷，苯，甲苯，二甲苯或萘烷，及鹵化之烴類，例如氯苯，二氯苯，二氯甲烷，氯仿，四氯甲烷，二氯乙烷或三氯乙烷，醚類，如二乙醚，二異丙醚，甲基第三丁醚，甲基第三戊醚，
二烷，四氫呋喃，1,2-二甲氧基乙烷，1,2-二乙氧基乙烷或苯甲醚；醇類，如甲醇，乙醇，異丙醇或丁醇，腈類，如乙腈，丙腈，正-或異丁腈或苄腈；醯胺類，如，N,N-二甲基甲醯胺，N,N-二甲基乙醯胺，N-甲基甲醯苯胺，N-甲基吡咯烷酮或六甲基磷醯胺；亞碸類，如二甲亞碸或碸類，如環丁碸。特別適宜者為，例如，乙腈，甲苯，二甲苯，氯苯，正己烷，環己烷或甲基環己烷，且特別佳者為，例如，乙腈，THF，甲苯或二甲苯。於該反應終止後，例如，將溶劑移除並將產物藉由過濾法單離，或首先將產物用水清洗並萃取，將有機相移除並將溶劑於減壓下移除。
然後，式(Ia)及(Ib)化合物，其中，R2等於(CO)OR5，可轉化為式(I)之吡唑酸，其中，R2等於COOH。
胺(IV)可於製備化合物(III)之方法中再利用。或者，其係藉由用酸洗滌反應混合物而截取。
本發明係藉由下列實例來闡明：
N-(1,1-二氟丙-2-亞基)丙-2-胺，(III-1)
於10℃時，於一含有二氟丙酮(94g，1mol)於500ml甲基第三丁醚(88g，1.5mol)之混合物中將異丙胺加入。1小時後，將(70g，0.5mol)BF3*Et2O加入並將混合物再攪拌1小時。將有機溶液與底部漿料分開並將溶劑於大氣壓力下蒸餾出來。將剩餘之液體於真空中蒸餾而得到139g酮亞胺，b.p.70-72℃/400mbar。
1H NMR(400MHz，CDCl3)：δ 5.9(t，1H)，3.7(m，1H)，1.8(s，3H)，1.1(d，6H)ppm。
19F(376MHz，CDCl3)1：δ -122(d，2F)ppm。
N-1,1-二氟丙-2-亞基-1-苯基甲胺，(III-2)
於10℃時，於一含有二氟丙酮(94g，1mol)於500ml甲苯之混合物中，緩
緩加入(107g，1mol)苄胺。於20℃達6小時後，將甲苯於減壓下蒸餾出來且該剩餘之液體未經純化即使用，170g。
1H NMR(400MHz，CDCl3)δ：7.2-7.4(m，5H)，5.9(t，1H)，4.5(s，2H)，2.0(s，3H)ppm。
19F(376MHz，CDCl3)1 δ：-1118(d，2F)ppm。
N-(1,1,1-三氟丙-2-亞基)丙-2-胺，(III-3)
製備法參見實例2，b.p.80-82℃。
N-1,1,1-三氟丙-2-亞基-1-苯基甲胺(III-4)
製備法參見實例2，b.p.90-91℃，1,5mbar。
3,5-雙(二氟甲基)吡唑，(I-1)
將一含有10.4(75mmol)N-(1,1-二氟丙-2-亞基)丙-2-胺及12g吡啶於100ml二氯甲烷之溶液冷卻至0℃。於此溫度時，將19.5g二氟醋酸酐於強烈攪拌時逐份加入，最後並將混合物於10℃攪拌6小時。將50ml HCl(呈5%水溶液)及將20g水合肼緩緩添加至反應溶液中以維持溫度低於40℃，並將混合物於40℃攪拌5小時。將100ml水及100ml二氯甲烷加入並將有機層分離，用水清洗，於MgSO4上乾燥並於真空中濃縮而得到一油性產物。於92-95℃/1mbar予以真空蒸餾而得到8.8g(70%)呈白色固體之純3,5-雙(二氟甲基)-1H-吡唑b)，m.p.70-71℃。
1H NMR(400MHz，CDCl3)δ：12.5(br，1H)，6.77(t，2H，J=54.8Hz)，6.74(s，1H)ppm。
3-(二氟甲基)-5-(三氟甲基)-1H-吡唑，(I-2)
類似的，由N-(1,1-二氟丙-2-亞基)丙-2-胺及三氟醋酸酐得到。
產率78%。
1H NMR(400MHz，CDCl3)δ：12.6(br，1H)，6.81(s，1H)，6.76(t，1H，J=54.5Hz)；13C(101MHz，CDCl3)1 δ：140.7，128.8，120.3(q，JC-F=266Hz)，108.5(t，JC-F=237Hz)，103.8；19F(376MHz，CDCl3)δ：-61.7(s，3F)，-112.9(d，2F，J=54.7Hz)；HRMS(ESI)C5H4F5N2[M+H]+計算值187.029，實測值187.029。
Claims (5)
- 一種製備式(Ia)及(Ib)3,5-雙(鹵烷基)吡唑之方法，其中，R1及R3 係各自獨立選自C1-C6-鹵烷基；R2 係選自H，鹵素，COOH，(C=O)OR5，CN及(C=O)NR6R7；R4 係選自H，C1-C8-烷基，芳基，吡啶基；R5 係選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基及C7-19-烷基芳基；R6及R7 係各自獨立選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基及C7-19-烷基芳基，或其中，R6及R7 與其等所鍵接之氮原子一起可形成一四-，五-或六員環，其特點在於，於步驟(A)中，式(II)之酸衍生物，
其中，R1 係定義如前；X 為F，Cl，Br或-OC(O)R1，係與式(III)化合物進行反應，
其中，R8 係選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基及C7-19-烷基芳基，OR9；R9係選自C1-12-烷基，C3-8-環烷基，C6-18-芳基，C7-19-芳基烷基，C7-19-烷基芳基；R2及R3係定義如前；而形成式(IV)化合物
其中，R1，R2，R3，R5，R6，R7，R8，R9 係定義如前，且於步驟(B)中，將(Ⅳ)在(V)NH2NHR4存在之下予以環化，其中，R4係定義如前，形成了(Ia)及(Ib)。
- 根據申請專利範圍第1項之製法，其特點在於R1及R3 係各自獨立選自二氟甲基，三氟甲基，氯氟甲基，二氯氟甲基，氯二氟甲基，1-氟乙基，2-氟乙基，2,2-二氟乙基，2,2,2-三氟乙基，2-氯-2-氟乙基，2-二氟乙基，2,2-二氯-2-氟乙基，2,2,2-三氯乙基，四氟乙基(CF3CFH)，五氟乙基及1,1,1-三氟丙-2-基；R2 係選自H，F，Cl，Br，COOCH3，COOC2H5，COOC3H7，CN及CON(CH3)2，CON(C2H5)2；R4 係選自H，C1-C8-烷基，芳基，吡啶基；R8 係各自獨立選自甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，環丙基，環丁基，環戊基，環己基，苯基，苄基，苯基乙基，甲苯基，2,3-，2,4-，2,5-，2,6-，3,4-或3,5-二甲基苯基；X 係選自F，Cl或-O(CO)R1。
- 根據申請專利範圍第1項之製法，其特點在於R1及R3 係各自獨立選自三氟甲基，二氟甲基，二氟氯甲基，五氟乙基；R2 係選自H，Cl，CN，COO(C2H5)2；R4 係選自H，甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，正戊基，正己基，1,3-二甲基丁基，3,3-二甲基丁基，芳基；R8 係選自甲基，乙基，正-，異丙基，正-，異-，新-及第三丁基，環丙基，環丁基，環戊基，環己基，苄基；X 係選自F，Cl或-OC(O)R1。
- 根據申請專利範圍第1項之製法，其特點在於R1及R3 係各自獨立選自CF2H，CF3；R2 係選自H或COOC2H5；R4 係選自H，甲基，乙基，苯基；R8 係選自乙基，正-，異丙基，正-，環戊基，環己基，苄基；X 為Cl或F。
- 根據申請專利範圍第1項之製法，其特點在於R1及R3 係各自獨立選自CF2H，CF3；R2 為H；R4 係選自H，甲基，苯基；R8 係選自異丙基，苄基；X 為Cl或F。
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| WO2013113829A1 (de) * | 2012-02-01 | 2013-08-08 | Bayer Cropscience Ag | Verfahren zur herstellung von 3,5-bis(fluoralkyl)-pyrazol-4-carbonsäure-derivaten und 3,5-bis(fluoralkyl)-pyrazolen |
| WO2014033164A1 (en) * | 2012-08-30 | 2014-03-06 | Bayer Cropscience Ag | Procedure for the decarboxylation of 3,5-bis(haloalkyl)-pyrazole-4-carboxylic acid derivatives |
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| BR112016028700B1 (pt) | 2021-03-23 |
| MX2016016399A (es) | 2017-04-06 |
| WO2015189138A1 (en) | 2015-12-17 |
| EP3154947A1 (en) | 2017-04-19 |
| JP6514722B2 (ja) | 2019-05-15 |
| JP2017517530A (ja) | 2017-06-29 |
| IL249282A0 (en) | 2017-02-28 |
| BR112016028700A2 (pt) | 2017-08-22 |
| CN106458918A (zh) | 2017-02-22 |
| ES2672581T3 (es) | 2018-06-15 |
| EP3154947B1 (en) | 2018-03-28 |
| DK3154947T3 (en) | 2018-06-18 |
| KR20170018885A (ko) | 2017-02-20 |
| CN106458918B (zh) | 2019-07-09 |
| US9914704B2 (en) | 2018-03-13 |
| IL249282B (en) | 2019-03-31 |
| US20170114020A1 (en) | 2017-04-27 |
| TW201613869A (en) | 2016-04-16 |
| KR102430607B1 (ko) | 2022-08-08 |
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