TWI428324B - 製備吡唑羧醯胺之方法 - Google Patents
製備吡唑羧醯胺之方法 Download PDFInfo
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- TWI428324B TWI428324B TW100113505A TW100113505A TWI428324B TW I428324 B TWI428324 B TW I428324B TW 100113505 A TW100113505 A TW 100113505A TW 100113505 A TW100113505 A TW 100113505A TW I428324 B TWI428324 B TW I428324B
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- Prior art keywords
- formula
- compound
- palladium
- ligand
- ferrocenyl
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- 238000000034 method Methods 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title description 13
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical class NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 64
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 55
- 239000003446 ligand Substances 0.000 claims description 55
- 229910052763 palladium Inorganic materials 0.000 claims description 26
- -1 phenyl lithium halides Chemical class 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 16
- 125000001246 bromo group Chemical group Br* 0.000 claims description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000002524 organometallic group Chemical group 0.000 claims description 4
- PGTKVMVZBBZCKQ-UHFFFAOYSA-N Fulvene Chemical compound C=C1C=CC=C1 PGTKVMVZBBZCKQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 12
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 8
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012696 Pd precursors Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DPOGTJDEMBEUSH-UHFFFAOYSA-N dicyclohexyl(ethyl)phosphane Chemical compound C1CCCCC1P(CC)C1CCCCC1 DPOGTJDEMBEUSH-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- AZZUOVGZUDIOAJ-UHFFFAOYSA-N imidazol-2-ylidenepalladium Chemical compound [Pd]=C1N=CC=N1 AZZUOVGZUDIOAJ-UHFFFAOYSA-N 0.000 description 5
- 150000002940 palladium Chemical class 0.000 description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000008096 xylene Substances 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
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- KCHQXPGUJBVNTN-UHFFFAOYSA-N 4,4-diphenylbut-3-en-2-one Chemical compound C=1C=CC=CC=1C(=CC(=O)C)C1=CC=CC=C1 KCHQXPGUJBVNTN-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- XUGHPTFNSLEKBM-UHFFFAOYSA-N cyclopenta-1,3-diene ditert-butyl-[1-(5-dicyclohexylphosphanylcyclopenta-1,4-dien-1-yl)ethyl]phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.CC(P(C(C)(C)C)C(C)(C)C)c1c[cH-]cc1P(C1CCCCC1)C1CCCCC1 XUGHPTFNSLEKBM-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RFXWSCVCWQKXAL-UHFFFAOYSA-N (3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P)=C1 RFXWSCVCWQKXAL-UHFFFAOYSA-N 0.000 description 2
- MKFCRMRYFGCWAZ-UHFFFAOYSA-N 1,2-dichloro-5-methylidenecyclopenta-1,3-diene Chemical compound ClC1=C(Cl)C(=C)C=C1 MKFCRMRYFGCWAZ-UHFFFAOYSA-N 0.000 description 2
- HVKCZUVMQPUWSX-UHFFFAOYSA-N 1-bromo-2,3-dichlorobenzene Chemical compound ClC1=CC=CC(Br)=C1Cl HVKCZUVMQPUWSX-UHFFFAOYSA-N 0.000 description 2
- QPUYECUOLPXSFR-UHFFFAOYSA-N 1-methylnaphthalene Chemical compound C1=CC=C2C(C)=CC=CC2=C1 QPUYECUOLPXSFR-UHFFFAOYSA-N 0.000 description 2
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- BMHUFYBSDMWTOX-UHFFFAOYSA-N 5-(dichloromethylidene)cyclopenta-1,3-diene Chemical compound ClC(Cl)=C1C=CC=C1 BMHUFYBSDMWTOX-UHFFFAOYSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- MAQJSOBHAZTNFV-UHFFFAOYSA-N C(C)(C)(C)P(C=1[C-](C=CC1)C(C)P(C1=C(C=CC=C1)C)C1=C(C=CC=C1)C)C(C)(C)C.[CH-]1C=CC=C1.[Fe+2] Chemical compound C(C)(C)(C)P(C=1[C-](C=CC1)C(C)P(C1=C(C=CC=C1)C)C1=C(C=CC=C1)C)C(C)(C)C.[CH-]1C=CC=C1.[Fe+2] MAQJSOBHAZTNFV-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- XQJHRCVXRAJIDY-UHFFFAOYSA-N aminophosphine Chemical compound PN XQJHRCVXRAJIDY-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- REDWELITTWIEQG-UHFFFAOYSA-N cyclopenta-1,3-diene;dicyclohexyl-[1-(2-diphenylphosphanylcyclopenta-2,4-dien-1-yl)ethyl]phosphane;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.C1=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)[C-]1C(C)P(C1CCCCC1)C1CCCCC1 REDWELITTWIEQG-UHFFFAOYSA-N 0.000 description 2
- HGTBZFMPHBAUCQ-KHZPMNTOSA-N cyclopentane;dicyclohexyl-[(1r)-1-(2-diphenylphosphanylcyclopentyl)ethyl]phosphane;iron Chemical compound [Fe].[CH]1[CH][CH][CH][CH]1.[C]1([C@@H](C)P(C2CCCCC2)C2CCCCC2)[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 HGTBZFMPHBAUCQ-KHZPMNTOSA-N 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- WDUDHEOUGWAKFD-UHFFFAOYSA-N ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+) Chemical compound [Fe+2].CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 WDUDHEOUGWAKFD-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- FJUVUVTZDIJSHX-UHFFFAOYSA-N 1,2-bis(1-adamantyl)-1h-imidazol-1-ium;chloride Chemical compound [Cl-].C1C(C2)CC(C3)CC2CC13C1=NC=C[NH+]1C(C1)(C2)CC3CC2CC1C3 FJUVUVTZDIJSHX-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- AVJBQMXODCVJCJ-UHFFFAOYSA-M 1,3-bis[2,6-di(propan-2-yl)phenyl]imidazol-1-ium;chloride Chemical compound [Cl-].CC(C)C1=CC=CC(C(C)C)=C1N1C=[N+](C=2C(=CC=CC=2C(C)C)C(C)C)C=C1 AVJBQMXODCVJCJ-UHFFFAOYSA-M 0.000 description 1
- DVDGHRQOLYEZAE-UHFFFAOYSA-N 1-n,1-n,2-n,2-n-tetramethylcyclohexane-1,2-diamine Chemical compound CN(C)C1CCCCC1N(C)C DVDGHRQOLYEZAE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BRPSAOUFIJSKOT-UHFFFAOYSA-N 2,3-dichloroaniline Chemical compound NC1=CC=CC(Cl)=C1Cl BRPSAOUFIJSKOT-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- DFGAJGVTKXZKID-UHFFFAOYSA-N 2-dicyclohexylphosphanyl-n,n-dimethyl-3-phenylaniline Chemical group C1CCCCC1P(C1CCCCC1)C=1C(N(C)C)=CC=CC=1C1=CC=CC=C1 DFGAJGVTKXZKID-UHFFFAOYSA-N 0.000 description 1
- DFURBSAMHSSUMC-UHFFFAOYSA-N 2-ditert-butylphosphanyl-n,n-dimethyl-3-phenylaniline Chemical group CN(C)C1=CC=CC(C=2C=CC=CC=2)=C1P(C(C)(C)C)C(C)(C)C DFURBSAMHSSUMC-UHFFFAOYSA-N 0.000 description 1
- RXFCIXRFAJRBSG-UHFFFAOYSA-N 3,2,3-tetramine Chemical compound NCCCNCCNCCCN RXFCIXRFAJRBSG-UHFFFAOYSA-N 0.000 description 1
- MZGPCLIDFPCPTI-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carbonyl chloride Chemical compound CN1C=C(C(Cl)=O)C(C(F)F)=N1 MZGPCLIDFPCPTI-UHFFFAOYSA-N 0.000 description 1
- XNXCINUKGNQCEZ-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxamide Chemical compound CN1C=C(C(N)=O)C(C(F)F)=N1 XNXCINUKGNQCEZ-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CAMMWBMHRDIZIN-UHFFFAOYSA-N N-(3-tricyclo[6.2.1.02,7]undeca-2(7),3,5-trienyl)methanimine Chemical compound C=NC1=CC=CC2=C1C3CCC2C3 CAMMWBMHRDIZIN-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical group C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012431 aqueous reaction media Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- XJIXVSYABXKOAQ-UHFFFAOYSA-N bis(1-adamantyl)-tert-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(C(C)(C)C)C1(C2)CC(C3)CC2CC3C1 XJIXVSYABXKOAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- XCJYREBRNVKWGJ-UHFFFAOYSA-N copper(II) phthalocyanine Chemical compound [Cu+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 XCJYREBRNVKWGJ-UHFFFAOYSA-N 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 1
- XUGHPTFNSLEKBM-GHVWMZMZSA-N cyclopenta-1,3-diene ditert-butyl-[(1R)-1-(2-dicyclohexylphosphanylcyclopenta-2,4-dien-1-yl)ethyl]phosphane iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.CC(C)(C)P(C(C)(C)C)[C@H](C)[C-]1C=CC=C1P(C1CCCCC1)C1CCCCC1 XUGHPTFNSLEKBM-GHVWMZMZSA-N 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- UIOXCPTYOYGESX-UHFFFAOYSA-N dibutyl(ethyl)phosphane Chemical compound CCCCP(CC)CCCC UIOXCPTYOYGESX-UHFFFAOYSA-N 0.000 description 1
- PTLIZOFGXLGHSY-UHFFFAOYSA-N dibutylphosphane Chemical compound CCCCPCCCC PTLIZOFGXLGHSY-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- QQSIRURWBGEHFS-UHFFFAOYSA-N ditert-butyl(oxo)phosphanium Chemical compound CC(C)(C)[P+](=O)C(C)(C)C QQSIRURWBGEHFS-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- OXTKXGVJXOBALA-UHFFFAOYSA-N ethyl-bis(2-methylphenyl)phosphane Chemical compound C=1C=CC=C(C)C=1P(CC)C1=CC=CC=C1C OXTKXGVJXOBALA-UHFFFAOYSA-N 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000003641 microbiacidal effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- OYJSZRRJQJAOFK-UHFFFAOYSA-N palladium ruthenium Chemical compound [Ru].[Pd] OYJSZRRJQJAOFK-UHFFFAOYSA-N 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Description
本發明係關於一種製備3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺之方法及適用於此方法之新穎中間物。
化合物3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺及其殺微生物性質描述於例如WO 2007/048556中。
3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺之製備自WO 2007/048556已知。該化合物可根據流程1及4由以下步驟來製備:
a)在亞硝酸烷酯存在下使式A化合物
,與式B化合物反應
,其中R'及R"為例如C1
-C4
烷基,形成式C化合物
b)在適合之金屬催化劑存在下使式C化合物氫化為式D化合物
c)用臭氧處理式D化合物,隨後用還原劑處理,形成式E化合物
d)在三苯基膦(triphenylphosphane)/四氯化碳存在下使式E化合物反應,形成式F之2,9-二氯亞甲基-5-硝基-苯并降冰片烯(benzonorbornene)
e)在金屬催化劑存在下使式F化合物氫化為式G之2,9-二氯亞甲基-5-胺基-苯并降冰片烯
f)及使式G化合物與式H化合物反應
形成3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺。
此先前技術方法之顯著缺點為難以大規模處置之臭氧分解反應。此外,大量反應步驟會降低方法之總產率並增加製造成本。該缺點使得此方法不經濟且尤其不適合於大規模生產。
因此,本發明之目標在於提供一種製備3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺之新穎方法,其避免已知方法之缺點且可以經濟上有利的方式以高產率及優良品質製備3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺。
因此,根據本發明,提供一種製備式I化合物之方法
該方法包含
a)在惰性氛圍下使式II化合物
其中X為氯基或溴基,與諸如C1-6
烷基-或苯基鋰或C1-6
烷基-或苯基鎂鹵化物之有機金屬物質反應,形成式III之鹵苯炔
其中X為氯基或溴基;使由此形成之式III之鹵苯炔與式IV之富烯反應
形成式V化合物
其中X為氯基或溴基;
b)在適合之金屬催化劑存在下使式V化合物氫化為式VI化合物
其中X為氯基或溴基;及
c1)在包含鈀及至少一種配位體之催化劑存在下使式VI化合物與NH3
反應,形成式VII化合物
及d)在鹼存在下使式VII化合物與式VIII化合物反應
形成該式I化合物;或
c2)在溶劑、鹼、銅催化劑及至少一種配位體存在下使式VI化合物
其中X為氯基或溴基,較佳為溴基,與式VIIIa化合物反應
形成該式I化合物。
反應步驟a):
X為溴基之式II化合物為已知的且揭示於例如Recueil des Travaux Chimiques des Pays-Bas,81,365(1962)中。X為氯基或溴基之式II化合物揭示於例如WO 2008/049507中。1-溴-2,3-二氯-苯可藉由所謂山德邁耳反應(Sandmeyer reaction)由2,3-二氯-苯胺製備。該等山德邁耳反應可藉由使用諸如亞硝酸第三丁酯或亞硝酸異戊酯之有機亞硝酸酯,在諸如乙腈之有機溶劑中,在作為溴化劑之溴化銅存在下(如Journal of Organic Chemistry,1977,42,2426-31中所述)來進行,或藉由包含在0℃至15℃之溫度下在酸性水性反應介質中使用無機亞硝酸鹽重氮化,接著將反應混合物添加至溴化亞銅溶液中的兩步反應(如Recueil des Travaux Chimiques des Pays-Bas et de la Belgique,1932,51,98-113及JP-6-2114-921中所述)來進行。
式IV之6,6-二氯-富烯(RN 35310-97-5)描述於Chemical Communications,20(1971),1293-1294中。
式V化合物為新穎的,特別開發用於本發明之方法,因此構成本發明之另一目標。
反應可在-78℃至20℃之溫度下,較佳在-20℃下進行。
反應在半分批或連續流動條件下,較佳在半分批條件下進行。
使用芳基鋰及烷基鋰化合物作為有機金屬物質來進行鋰鹵素交換,例如苯基鋰、甲基鋰或正丁基鋰,較佳為正丁基鋰。
使用非質子性溶劑作為溶劑,較佳為烴,如甲苯。
較佳經15至180分鐘向二氯富烯於溶劑中之溶液中給與烷基鋰與三鹵基苯,然而,亦可向三鹵基苯及式IV化合物於溶劑中之混合物給與烷基鋰。亦可向三鹵基苯於溶劑中之溶液給與烷基鋰及式IV化合物。
通常在完成相應試劑添加後15至180分鐘完全轉化。
反應步驟b):
式VI化合物可藉由使用雷氏鎳(Raney Nickel)(或載於載劑上或與配位體組合之Rh、Pd、Ir、Pt、Co及Fe催化劑)選擇性還原非氯化雙鍵來製備。反應可在大氣壓力下或在高氫氣壓力下,較佳在大氣壓力下進行。
反應可在周圍溫度或高溫下,較佳在周圍溫度下,尤其在20℃至25℃下進行。
反應在對雷氏鎳呈惰性之溶劑中進行。較佳溶劑為乙酸乙酯。
式VI化合物為新穎的,特別開發用於本發明之方法,因此構成本發明之另一目標。
反應步驟c1):
自兩種方法變化形式步驟c1)至步驟d)及步驟c2),變化形式步驟c1)至d)為較佳。方法中所用之包含鈀及至少一種配位體之催化劑一般將由鈀前驅物及至少一種適合之配位體形成。在方法在溶劑中進行之情況下,錯合物通常將可溶於溶劑中。在此方法之上下文中,鈀錯合物明確地包括由環狀有機鈀化合物(「鈀環」)及二級膦配位體組成之錯合物。
鈀錯合物可以穩固、預形成之物質形式使用或可當場形成。典型地,其藉由使鈀前驅物與至少一種適合之配位體反應來製備。在不完全轉化之情況下,剩餘量之鈀前驅物或配位體可以不溶於反應混合物中之形式存在。
適用之鈀前驅物可選自乙酸鈀、氯化鈀、氯化鈀溶液、鈀2
-(二苯亞甲基丙酮)3
或鈀-(二苯亞甲基丙酮)2
、鈀-肆(三苯基膦)、鈀/碳、鈀二氯-雙(苯甲腈)、鈀-(參-第三丁基膦)2
或鈀2
-(二苯亞甲基丙酮)3
與鈀-(參-第三丁基膦)2
之混合物。
適用之配位體為例如三級膦配位體、N
-雜環碳烯配位體及膦酸配位體。三級膦配位體一般具有兩個類型:單牙配位體及雙牙配位體。單牙配位體可佔據一個鈀配位點,而雙牙配位體佔據兩個配位點,因此能夠螯合鈀物質。
以下為三級膦、N
-雜環碳烯及膦酸配位體以及具有二級膦配位體之鈀環的實例。
(A)單牙膦配位體:
三第三丁基膦、四氟硼酸三第三丁基鏻(「P(tBu)3
HBF4
」)、參鄰甲苯基膦(「P(oTol)3
」)、參-環己基膦(「P(Cy)3
」)、2-二第三丁基-膦基-1,1'-聯苯(「P(tBu)2
BiPh」)、2-二環己基-膦基-1,1'-聯苯(「P(Cy)2
BiPh」)、2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯(「x-Phos」)及第三丁基-二-1-金剛烷基-膦(「P(tBu)(Adam)2
」)。
關於單牙膦配位體之更多資訊可見於US-2004-0171833中。
(B)雙牙三級膦配位體:
(B1)雙膦配位體:
(B1.1)二茂鐵基-雙膦配位體(「Josiphos」配位體):
1,1'-雙(二苯基膦基)二茂鐵(dppf)、1,1'-雙(二第三丁基膦基)-二茂鐵、(R)-(-)-1-[(S)-2-(雙(4-三氟甲基苯基)膦基)二茂鐵基]乙基-二第三丁基膦、(R)-(-)-1-[(S)-2-(二(3,5-雙-三氟甲基苯基)膦基)二茂鐵基]乙基二環己基膦、(R)-(-)-1-[(S)-2-(二(3,5-雙-三氟甲基苯基)膦基)二茂鐵基]乙基二(3,5-二甲基苯基)膦、(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦、(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二環己基膦、(S)-(+)-1-[(R)-2-(二環己基膦基)二茂鐵基]乙基二環己基膦、(S)-(+)-1-[(R)-2-(二環己基膦基)二茂鐵基]乙基二苯基膦、(R)-(-)-1-[(S)-2-(雙(3,5-二甲基-4-甲氧基苯基)膦基)二茂鐵基]乙基二環己基膦、(S)-(+)-1-[(R)-2-(二呋喃基膦基)二茂鐵基]乙基二-3,5-二甲苯基膦、(R)-(-)-1-[(S)-2-(二苯基膦基)二茂鐵基]乙基二第三丁基膦、(S)-(+)-1-[(R)-2-(二苯基膦基)二茂鐵基]乙基二第三丁基膦、(R)-(-)-1-[(S)-2-(二苯基膦基)二茂鐵基]乙基二環己基膦、(R)-(+)-1-[(R)-2-(二苯基膦基)二茂鐵基]乙基二環己基膦、(S)-(+)-1-[(R)-2-(二苯基膦基)二茂鐵基]乙基二環己基膦、(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二苯基膦、(R)-(-)-1-[(S)-2-(二苯基)膦基)二茂鐵基]乙基二(3,5-二甲基苯基)膦、(R)-(-)-1-[(S)-2-(二第三丁基-膦基)二茂鐵基]乙基-二鄰甲苯基膦
(R)-(-)-1-[(S)-2-(雙(3,5-二甲基-4-甲氧基苯基)膦基)二茂鐵基]-乙基-二第三丁基膦
(R)-(-)-1-[(S)-2-(二乙基膦基)二茂鐵基]-乙基-二第三丁基膦
(R)-(-)-1-[(S)-2-(P
-甲基-P
-異丙基-膦基)二茂鐵基]乙基二環己基膦
(R)-(-)-1-[(S)-2-(P
-甲基-P
-苯基-膦基)二茂鐵基]乙基-二第三丁基膦
及其外消旋混合物,尤其為1-[2-(二第三丁基膦基)二茂鐵基]乙基-二鄰甲苯基膦、1-[2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦及1-[2-(二苯基膦基)二茂鐵基]乙基二環己基膦之外消旋混合物。
(B1.2)聯萘-雙膦配位體:
2,2'雙(二苯基膦基)-1,1'-聯萘(「BINAP」)、R-(+)-2,2'-雙(二對甲苯基膦基)-1,1'-聯萘(「Tol-BINAP」)、外消旋2,2'-雙(二對甲苯基膦基)-1,1'-聯萘(「外消旋Tol-BINAP」)。
(B1.3)9,9-二甲基-4,5-雙(二苯基-膦基)-二苯并哌喃(「Xantphos」)。
(B2)胺基膦2配位體:
(B2.1)聯苯配位體:
2-二環己基膦基-(N,N
-二甲基胺基)-1,1'-聯苯(「PCy2
NMe2
BiPh」)
2-二第三丁基膦基-(N,N
-二甲基胺基)-1,1'-聯苯(「P(tBu)2
NMe2
BiPh」)。
(C)N
-雜環碳烯配位體:
氯化1,3-雙(2,6-二異丙基苯基)-咪唑鎓(「I-Pr」)、氯化1,2-雙(1-金剛烷基)-咪唑鎓(「I-Ad」)及氯化1,3-雙(2,6-甲基苯基)-咪唑鎓(「I-Me」)。
(D)膦酸配位體:
二第三丁基-膦氧化物。
(E)含有二級膦配位體之鈀環:
式(A-1)之錯合物
其中「norb」為降冰片基,及式(A-2)之錯合物
鈀錯合物(A-1)以代號「SK-CC01-A」描述於Synlett
.,2549-2552(2004)中。錯合物(A-2)以代號「SK-CC02-A」描述於Synlett.
(同前
)中。
含有膦酸配位體之鈀錯合物之其他實例以代號「POPd」、「POPd2」及「POPD1」描述於J. Org. Chem.
66,8677-8681中。
含有N
-雜環碳烯配位體之鈀錯合物的其他實例為萘醌-1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基-鈀(「[Pd-NQ-IPr]2
」)、二乙烯基-四甲基矽氧烷-1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基-鈀(「Pd-VTS-IPr」)、二氯化1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基-鈀(「Pd-Cl-IPr」)、二乙酸1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基-鈀(「Pd-OAc-IPr」)、氯化烯丙基-1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基-鈀(「Pd-Al-Cl-IPr」)及式(A-3)化合物:
其中R5
為2,6-二異丙基苯基或2,4,6-三甲基苯基。關於[Pd-NQ-IPr]2
、Pd-VTS-IPr、Pd-Cl-IPr、Pd-OAc-IPr及Pd-Al-Cl-IPr之更多資訊可見於Organic Letters
,4,2229-2231(2002
)及Synlett
.,275-278,(2005
)中。關於式(A-3)化合物之更多資訊可見於Organic Letters
,5,1479-1482(2003
)中。
單一鈀錯合物或不同鈀錯合物之混合物可用於製備通式(VII)化合物之方法中。
尤其適用於形成鈀錯合物之鈀前驅物為選自以下之鈀前驅物:乙酸鈀、鈀2
-(二苯亞甲基丙酮)3
、鈀-(二苯亞甲基丙酮)2
、氯化鈀溶液或鈀2
-(二苯亞甲基丙酮)3
與鈀-(參-第三丁基膦)2
之混合物。乙酸鈀尤其適用,氯化鈀亦適用。
使用至少一種配位體來形成鈀錯合物。通常,鈀錯合物具有至少一種選自單牙三級膦配位體、雙牙三級膦配位體及N
-雜環碳烯配位體之配位體,及典型地至少一種選自二茂鐵基-雙膦配位體、聯萘-雙膦配位體及胺基膦配位體之配位體。
尤其適合的是含有至少一種選自以下之配位體的鈀錯合物:三第三丁基膦、P(tBu)3
HBF4
、P(oTol)3
、P(Cy)3
、P(tBu)2
BiPh、P(Cy)2
BiPh、x-Phos、P(tBu)(Adam)2
、(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦、外消旋1-[2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦、(R)-(-)-1-[(S)-2-(二第三丁基-膦基)二茂鐵基]乙基二鄰甲苯基膦、外消旋1-[2-(二第三丁基-膦基)二茂鐵基]乙基二鄰甲苯基膦、dppf、1,1'-雙(二第三丁基膦基)-二茂鐵、(R)-(-)-1-[(S)-2-(二苯基膦基)二茂鐵基]乙基二環己基膦、外消旋1-[2-(二苯基膦基)二茂鐵基]乙基二環己基膦、(R)-(-)-1-[(S)-2-(二苯基膦基)二茂鐵基]乙基二第三丁基膦、BINAP、Tol-BINAP、外消旋Tol-BINAP、Xantphos、PCy2
NMe2
BiPh、P(tBu)2
NMe2
BiPh、I-Pr、I-Ad及I-Me,以及式(A-3)之鈀錯合物,其中R5
為2,6-二異丙基苯基或2,4,6-三甲基苯基。
較佳為含至少一種選自以下之配位體的鈀錯合物:三第三丁基膦、P(tBu)3
HBF4
、P(tBu)2
BiPh、P(Cy)2
BiPh、x-Phos、(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦、外消旋1-[2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦、(R)-(-)-1-[(S)-2-(二第三丁基膦基)二茂鐵基]乙基二鄰甲苯基膦、外消旋1-[2-(二第三丁基-膦基)二茂鐵基]乙基二鄰甲苯基膦、dppf、PCy2
NMe2
BiPh及I-Pr。
特別受關注的是含有至少一種選自以下各組之配位體的鈀錯合物:
(i)三第三丁基膦、P(tBu)3
HBF4
、P(tBu)2
BiPh、P(Cy)2
BiPh、x-Phos、PCy2
NMe2
BiPh及I-Pr;
(ii)三第三丁基膦、P(tBu)3
HBF4
、PCy2
NMe2
BiPh及I-Pr;
(iii)三第三丁基膦及P(tBu)3
HBF4
;及
(iv)(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦及外消旋1-[2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦。
較佳為含有作為配位體之PCy2
NMe2
BiPh、I-Pr、(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦或外消旋1-[2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦的鈀錯合物。
較佳錯合物為前驅物為氯化鈀且配位體為(R)-(-)-1-[(S)-2-(二環己基膦基)二茂鐵基]乙基二第三丁基膦之錯合物。
製備式(II)化合物中使用催化量之鈀錯合物,通常相對於式(IV)化合物之莫耳比為1:10至1:10000,典型地比率為1:100至1:1000,例如1:500至1:700或約1:600。錯合物可預形成或當場由前驅物與配位體混合在一起而形成,兩者一般以等莫耳量或約等莫耳量使用。
用於反應步驟f)之尤其較佳鈀催化劑為Pd(OAc)2
(較佳負載為3-5 mol%,尤其為4 mol%);選自Josiphos、DavePhos(例如2-二環己基膦基-2'-(N,N
-二甲基胺基)聯苯)或Xantphos 4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃)型之配位體,較佳為Josiphos型,尤其為Josiphos SL-J009-1,其為(2R
)-1-[(1R
)-1-[雙(1,1-二甲基乙基)膦基]乙基]-2-(二環己基膦基)二茂鐵(較佳量為3-5 mol%,尤其為4.4 mol%)。
宜在0.9 MPa至1.1 MPa、較佳1 MPa至1.05 MPa之壓力下添加NH3
。
反應步驟較佳在80℃至150℃、較佳100℃至120℃之溫度,1.4 MPa至2.6 MPa、較佳1.5 MPa至2.2 MPa、尤其2.2 MPa之壓力下進行。較佳溶劑為醚,如二甲醚。
反應步驟d):
式VIII化合物為已知的且揭示於例如US-5,093,347中。
用於反應步驟d)之較佳鹼為胺,如三乙胺,或碳酸鈉或碳酸鉀或碳酸氫鈉或碳酸氫鉀,或NaOH,較佳為三乙胺或NaOH。
較佳溶劑為二甲苯、甲苯或氯苯。反應較佳在-10℃至90℃、較佳70℃至80℃之溫度下進行。
反應步驟c2):
式VIIIa化合物描述於例如PCT/EP2009/067286中。
反應步驟c2)可在100℃至180℃之溫度下、較佳在130℃下進行。可在密封小瓶、敞口燒瓶中,在回流下或在微波照射下,較佳在密封小瓶中進行加熱。
可使用以下作為溶劑:醯胺(DMF、NMP)、醇(環己醇)、醚(二乙二醇二甲醚、二噁烷)、亞碸(DMSO)、烴(均三甲苯、甲苯)、腈(丁腈)及其混合物(甲苯/甲醇、甲苯/環己醇、二噁烷/甲醇、二噁烷/水),較佳為甲苯及二噁烷。
可使用Cu(0)、Cu(I)或Cu(II)鹽作為銅來源。實例為Cu(0)粉、碘化銅(I)、噻吩羧酸銅(I)、銅(II)酞菁、乙酸銅(II)、氧化銅(II)、氯化銅(II)、溴化銅(II)、五水合硫酸銅(II)及其混合物,較佳為氧化銅(II)及氯化銅(II)。
銅催化劑之用量可介於2 mol-%與330 mol-%之間,較佳為8-12 mol-%,尤其為10 mol-%。若使用Cu(0),則該量較佳>100 mol%。有效催化一般需要配位體。實例為N,N'
-二甲基伸乙基二胺、1,2-雙-二甲基胺基環己烷、1,2-二胺基環己烷、1,2-苯二胺、4-二甲基胺基吡啶、1,2-雙(3-胺基丙基胺基)乙烷、三伸乙基四胺、二伸乙基三胺、參(2-胺基乙基)胺。較佳使用N,N'
-二甲基伸乙基二胺。可使用碳酸鹽作為鹼,例如碳酸銫且較佳為碳酸鉀。一般在5-24小時後完成轉化。
製備實施例:
步驟a):製備式Va之5-氯-9-二氯亞甲基-1,4-二氫-1,4-亞甲基-萘:
在-20℃下經30分鐘將50% 1,2-二氯-3-溴苯之甲苯溶液(45.2 g,0.10 mol)及時間延遲5分鐘後2.7 Mn
BuLi之庚烷溶液(41 ml,0.11 mmol)添加至10%二氯富烯之甲苯溶液(77.3 g,0.06 mol)。再攪拌反應混合物1小時,隨後進一步添加n
BuLi之等分試樣(4.1 mL,0.01 mol)且再攪拌反應混合物15分鐘。隨後,添加nBuLi之第三等分試樣(4.1 ml,0.01 mol)以使得完全轉化。攪拌15分鐘時間後,用飽和NH4
Cl水溶液中止反應混合物。用水萃取有機層兩次,用鹽水萃取一次且經Na2
SO4
脫水。產率:60%。
1 H NMR
(400 MHz,CDCl3
): δ 4.49-4.50(m,1H,CH
),4.70-4.71(m,1H,CH
),6.90-6.94(m,2H,H
C=CH
),6.94-7.02(m,2H,Ph-H
),7.15(br d,J
(H,H)=8.0 Hz,1H,Ph-H
)。
13 C{ 1 H} NMR
(100 MHz,CDCl3
): δ 50.9(C
H),53.0(C
H),101.0(C (q)
Cl2
),120.1(Ph
-H),126.4(Ph
-H),127.2(Ph
-H),127.9(C
CCl2
),141.4(HC
=CH),142.4(HC=C
H),145.7(Ph (q)
),149.9(Ph (q)
),159.9(Ph (q)
)。
可類似地製備式Vb之化合物5-溴-9-二氯亞甲基-1,4-二氫-1,4-亞甲基-萘
1 H NMR
(400 MHz,CDCl3
): δ 4.52-4.54(m,1H,CH
),4.65-4.66(m,1H,CH
),6.90(dd,J
(H,H)=8 Hz,J
(H,H)=8 Hz,1H,Ph-H
),6.91-6.96(m,2H,H
C=CH
),7.16(d,J
(H,H)=8 Hz,1H,Ph-H
),7.17(d,J
(H,H)=8 Hz,1H,Ph-H
)。
步驟b):製備式VIa之5-氯-9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘:
將雷氏鎳(1.5 g)添加至式Va化合物(5.4 g,18.6 mmol)於乙酸乙酯(75 ml)中之溶液中。用氫氣吹掃溶液上方的氛圍且將填充氫氣之氣球置於反應容器頂部。在周圍溫度下攪拌4小時時段後,再將等分雷氏鎳(1.5 g)添加至反應溶液中且攪拌18小時。反應溶液經纖維素過濾。藉由管柱層析法(己烷)純化粗產物。產率:74%。
1 H NMR
(400 MHz,CDCl3
): δ 1.30-1.45(m,2H,CH 2
),2.07-2.15(m,2H,CH 2
),3.98(br d,J
(H,H)=4 Hz,1H,CH
),4.19(br d,J
(H,H)=4 Hz,1H,CH
),7.05-7.15(m,3H,Ph-H
)。
13 C{ 1 H} NMR
(100 MHz,CDCl3
): δ 25.5(C
H2
),26.5(C
H2
),45.4(C
H),47.5(C
H),104.3(C (q)
Cl2
),118.7(Ph
-H),126.8(Ph
-H),126.9(C
CCl2
),127.9(Ph
-H),142.5(Ph (q)
),146.7(Ph (q)
),150.7(Ph (q)
)。
步驟c1):以5-溴-9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘作為起始物質來製備式VII之9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基胺:
催化劑製備:將8.98 mg乙酸鈀(0.040 mmol)及22 mg Josiphos配位體(Josiphos SL-J009-1,(2R
)-1-[(1R
)-1-[雙(1,1-二甲基乙基)膦基]乙基]-2-(二環己基膦基)二茂鐵(Solvias AG),0.040 mmol)置於5 ml施蘭克管(Schlenk tube)中且用氬氣/真空變成惰性。添加2.5 ml二甲醚且攪拌催化劑15分鐘。
起始物質溶液:將608 mg 5-溴-9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘(2 mmol)置於5 ml施蘭克管中且用氬氣/真空變成惰性。接著將2.5 ml經脫氣之二甲醚添加至起始物質中。
反應:將384 mg NaOtBu(4 mmol)置於50 ml不鏽鋼高壓釜中。將該高壓釜擰上且置於氬氣下。在恆定氬氣流下,將起始物質溶液轉移至高壓釜中,隨後轉移催化劑溶液。添加NH3
,直至壓力達到1.05 MPa。將高壓釜加熱至105℃,壓力增加至1.6 MPa。反應32小時後,停止反應。藉由HPLC鑑別出79%產物。
式VII化合物可類似地用5-氯-9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘作為起始物質來製備。
步驟d):製備式I之3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺:
將9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基胺(166g,35%二甲苯溶液,0.25 mol)、三乙胺(28 g,0.275 mol)及二甲苯(13 g)裝入反應器中且將混合物加熱至80℃。經2小時添加3-二氟甲基-1-甲基-1H-吡唑-4-羰基氯(182 g,26%二甲苯溶液,0.25 mol)。轉化後,萃取產物,濃縮且在二甲苯/甲基環己烷之混合物中結晶。分離出83 g純產物。(純度:97%,產率:82%)。
1
H-NMR(400 MHz,CDCl3
): δ=8.12(bs,1H,NH);8.05(s,1H,Pyr-H);7.83-7.80(d,1H,Ar-H);7.19-7.15(t,1H,Ar-H);7.04(d,1H,Ar-H);7.02-6.76(t,1H,CHF2
);4.1(s,1H,CH);3.95-4.0(bs,4H,CH及CH3
);2.18-2.08(m,2H,CH2
);1.55-1.3(2m,2H,CH2
)。
步驟c2):製備式I之3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘-5-基)-醯胺:
用以下固體填充20 ml螺旋蓋小瓶:CuO(0.05 mmol,4.0 mg)、無水CuCl2
(0.05 mmol,6.7 mg)、K2
CO3
(2.0 mmol,277 mg)、3-二氟甲基-1-甲基-1H-吡唑-4-甲醯胺(1.1 mmol,193 mg)及5-溴-9-二氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘(1.0 mmol,304 mg)。添加磁力攪拌棒,且用N2
輕輕沖洗敞口小瓶。添加二噁烷(2 mL),隨後添加N,N'
-二甲基伸乙基二胺(0.45 mmol,48 μl)。密封該小瓶且置於在130℃下預加熱之篩選區塊中。24小時後完成轉化。式I化合物之產率(HPLC分析)為70%。
反應可類似地使用5,9,9-三氯亞甲基-1,2,3,4-四氫-1,4-亞甲基-萘作為起始物質來進行。
Claims (6)
- 一種製備式I化合物之方法
- 如申請專利範圍第1項之方法,其中在步驟a)中該有機金屬物質選自C1-6 烷基-或苯基鋰鹵化物及C1-6 烷基-或苯基鎂鹵化物。
- 如申請專利範圍第1項之方法,其中在步驟c)中該配位體選自二茂鐵基-雙膦配位體。
- 如申請專利範圍第1項之方法,其包含在包含鈀及至少一種配位體之催化劑存在下使該式VI化合物與NH3 反應,形成該式VII化合物
- 一種式V化合物
- 一種式VI化合物
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