CN111372919A - 制备氟吡菌胺的方法 - Google Patents
制备氟吡菌胺的方法 Download PDFInfo
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- CN111372919A CN111372919A CN201880075508.4A CN201880075508A CN111372919A CN 111372919 A CN111372919 A CN 111372919A CN 201880075508 A CN201880075508 A CN 201880075508A CN 111372919 A CN111372919 A CN 111372919A
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 239000005782 Fluopicolide Substances 0.000 title claims abstract description 7
- GBOYJIHYACSLGN-UHFFFAOYSA-N fluopicolide Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CNC(=O)C1=C(Cl)C=CC=C1Cl GBOYJIHYACSLGN-UHFFFAOYSA-N 0.000 title claims abstract description 7
- -1 pyridylmethyl benzamide derivatives Chemical class 0.000 claims abstract description 26
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 11
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 239000008346 aqueous phase Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 7
- 239000000920 calcium hydroxide Substances 0.000 claims description 7
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
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- 238000010438 heat treatment Methods 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical class NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 abstract description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 229910052801 chlorine Inorganic materials 0.000 description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 229910052759 nickel Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical class N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
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- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- CBXWGGFGZDVPNV-UHFFFAOYSA-N so4-so4 Chemical compound OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NVJUHMXYKCUMQA-UHFFFAOYSA-N 1-ethoxypropane Chemical compound CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004781 2,2-dichloro-2-fluoroethyl group Chemical group [H]C([H])(*)C(F)(Cl)Cl 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- CUDYYMUUJHLCGZ-UHFFFAOYSA-N 2-(2-methoxypropoxy)propan-1-ol Chemical compound COC(C)COC(C)CO CUDYYMUUJHLCGZ-UHFFFAOYSA-N 0.000 description 1
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- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- XSJVWZAETSBXKU-UHFFFAOYSA-N 2-ethoxypropane Chemical compound CCOC(C)C XSJVWZAETSBXKU-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
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- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000003032 phytopathogenic effect Effects 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及一种改进的制备式(I)的取代的吡啶基甲基苯甲酰胺衍生物、特别是2,6‑二氯‑N‑{[3‑氯‑5‑(三氟甲基)‑2‑吡啶基]甲基}苯甲酰胺(氟吡菌胺)的方法,其通过阮内镍氢化而获得的取代的2‑(氨基甲基)吡啶衍生物制备。
Description
本发明涉及一种改进的制备式(I)的取代的吡啶基甲基苯甲酰胺衍生物、特别是2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲酰胺(氟吡菌胺(Fluopicolide))的方法,其由通过阮内镍氢化而获得的取代的2-(氨基甲基)吡啶衍生物制备。
背景技术
式(I)的取代的吡啶基甲基苯甲酰胺衍生物对植物病原真菌具有高活性,
其中
p为等于1、2、3或4的整数,
q为等于1、2、3或4的整数,
X独立地选自氢、卤素、(C1-C4)-烷基和(C1-C4)-卤代烷基,条件是至少一个X为卤素,
Y为卤素。
式(I)的化合物记载于EP1056723B1中。
取代的2-(氨基甲基)吡啶衍生物,例如特别是3-氯-2-氰基-5-三氟甲基吡啶,是制备下面所示的式(Ia)的氟吡菌胺(2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲酰胺)——市售可得的杀真菌剂——的重要中间体
取代的2-(氨基甲基)吡啶衍生物的制备在现有技术中是已知的。WO 99/42447和WO 2004/65359记载了通过取代的亚胺衍生物形成取代的吡啶基甲基苯甲酰胺衍生物。该方法涉及数个步骤,因此效率不高。WO 2002/016322公开了通过在木炭载钯的存在下,使相应的取代的2-氰基吡啶衍生物氢化而制备取代的2-(氨基甲基)吡啶衍生物。然而,该方法具有几个缺点,例如氢化步骤的收率低、脱卤副产物的形成、2-(氨基甲基)吡啶衍生物的分离以及所分离材料的稳定性问题。WO 2004/046114公开了在乙酸中在阮内镍的存在下,将取代的2-氰基吡啶衍生物催化氢化为相应的2-(氨基甲基)吡啶衍生物。通常,腈的催化氢化在文献中是众所周知的,并且可用不同的镍催化剂进行(Nishimura,“Handbook ofHeterogeneous Catalytic Hydrogenation for Organic Synthesis”,第259-285页,JohnWiley and Sons,New York,2001)。还已知将腈催化氢化为所需的伯胺通常伴随着大量仲胺和叔胺的形成,所述仲胺和叔胺污染了所需的伯胺,并使分离非常复杂、昂贵且效率低下,因此不适于在工业规模上使用。出人意料地,WO 2004/046114中记载的方法不会导致形成不需要的副产物,因此WO 99/42447、WO 2004/6535和WO 2002/016322中公开的方法的良好替代方案。然而,如WO 2004/046114中所述的在阮内镍的存在下,通过氢化还原取代的2-氰基吡啶衍生物具有极大的缺点,即所得的2-(氨基甲基)吡啶衍生物以及随后的取代的吡啶基甲基苯甲酰胺衍生物由于所谓的镍浸出而被镍污染至对于农产品而言无法接受的程度。因此,所描述的现有技术方法非常不适于大规模生产。WO 99/42447中记载的形成式(I)的取代的吡啶基甲基苯甲酰胺衍生物的方法不适于大规模生产。
因此,本发明的目的是提供一种新的、改进的、技术上可行的、经济上和环境上更可行的方法,其适于在工业规模上由通过阮内镍氢化而获得的取代的2-(氨基甲基)吡啶衍生物制备取代的吡啶基甲基苯甲酰胺衍生物。
如下文中详细描述的,本发明的新方法提供经济的、技术上容易实行的方法,其解决了现有技术中记载的方法的上述问题,因此适于在工业规模上由通过阮内镍氢化而获得的取代的2-(氨基甲基)吡啶衍生物制备镍含量显著降低的取代的吡啶基甲基苯甲酰胺衍生物。
本发明的目的是一种方法
[A]用于制备式(I)的取代的吡啶基甲基苯甲酰胺衍生物或其盐,
其中
p为等于1、2、3或4的整数,
q为等于1、2、3或4的整数,
X独立地选自氢、卤素、(C1-C4)-烷基和(C1-C4)-卤代烷基,条件是至少一个X为卤素,
Y为卤素,
其特征在于,其包括以下步骤
[A1]使式(III)的取代的2-(氨基甲基)吡啶基衍生物或其盐,在合适的溶剂中,在合适的碱的存在下,在0℃至+50℃的温度下,与式(IV)的化合物反应,
其中p和X如上定义,并且
其中式(III)的化合物通过阮内镍氢化而获得,
其中
q为等于1、2、3或4的整数,
Y为卤素,并且
L1为离去基团,
[A2]将所得反应混合物加热至+70℃至+90℃的温度,
[A3]用合适的酸酸化反应混合物至pH值为0至3,
[A4]分离各相,并弃去水相,
[A5]加入水和合适的碱,将pH值调节为4至6,
[A6]分离各相,并弃去水相,
[A7]将反应混合物缓慢冷却至0℃至+10℃,
[A8]过滤反应混合物,用合适的溶剂洗涤滤饼,并干燥湿的滤饼,以得到式(I)的化合物或其盐。
在另一个实施方案中,方法[A]在步骤[A4]之后还包括其他步骤[A4a]和[A4b]
其中
[A4a]加入水和合适的酸,以将pH值调节为0至3,
[A4b]分离各相,并弃去水相。
除非另有说明,否则以下定义适用于整个说明书和权利要求书中使用的取代基和残基。
式(I)的化合物的相应盐优选为硫酸氢盐、硫酸盐、硫酸氢盐-硫酸盐混合物、盐酸盐、磷酸盐、甲酸盐或乙酸盐。
式(III)的化合物的相应盐优选为硫酸氢盐、硫酸盐、硫酸氢盐-硫酸盐混合物、盐酸盐、磷酸盐、甲酸盐或乙酸盐。特别优选乙酸盐。
在整个发明中,术语当量是指摩尔当量。
烷基代表具有1至4个碳原子的直链或支链饱和烃基。非限制性实例包括甲基、乙基、丙基、1-甲基乙基(异丙基)、正丁基、1-甲基丙基(异丁基)、2-甲基丙基(仲丁基)、1,1-二甲基乙基(叔丁基)。优选(C1-C2)-烷基,其代表具有1或2个碳原子的直链饱和烃基,例如甲基或乙基。
卤代烷基通常代表具有1至4个碳原子的烷基,其中1至所有氢原子被卤素原子取代。非限制性实例包括氯甲基、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-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、3-氯-1-甲基丁基、2-氯-1-甲基丁基、1-氯丁基、3,3-二氯-1-甲基丁基、3-氯-1-甲基丁基、1-甲基-3-三氟甲基丁基、3-甲基-1-三氟甲基丁基。优选二氟甲基、三氟甲基、二氯甲基、三氯甲基。
优选地,X独立地选自氟、氯、溴、甲基、乙基和具有1至5个卤素原子的(C1-C2)-卤代烷基,所述卤素原子独立地选自氟和氯。
更优选地,X独立地选自氟、氯、甲基、乙基或具有1至5个卤素原子的(C1-C2)-卤代烷基,所述卤素原子独立地选自氟和氯。
特别优选地,X独立地选自氟、氯、二氟甲基、三氟甲基、二氯甲基和三氯甲基。
非常特别优选地,X独立地选自氯和三氟甲基。
特别优选地,2-吡啶基部分在3位和5位被X取代。
非常特别优选地,式(III)的化合物为式(IIIa)的1-[3-氯-5-(三氟甲基)吡啶-2-基甲胺乙酸盐
优选地,Y独立地选自氟、氯和溴。
更优选地,Y独立地选自氟和氯。
特别优选地,Y为氯。
更优选地,苯甲酰基部分在2位和6位被X取代。
特别优选地,式(IV)的化合物为式(IVa)的2,6-二氯苯甲酰氯
优选地,p为等于1、2或3的整数。
更优选地,p为等于1或2的整数。
特别优选地,p为等于2的整数。
优选地,q为等于1、2或3的整数。
更优选地,q为等于1或2的整数。
特别优选地,q为等于2的整数。
优选地,离开基团L1为卤素。
更优选地,离去基团L1选自氯、溴和碘。
特别优选地,离去基团L1为氯。
非常特别优选地,式(I)的化合物为式(Ia)的氟吡菌胺
特别优选地,本发明的目的是一种制备式(Ia)的取代的吡啶基甲基苯甲酰胺的方法[A]
其特征在于,其包括以下步骤
[A1]使式(IIIa)的取代的2-(氨基甲基)吡啶基衍生物,在合适的溶剂中,在合适的碱的存在下,在0℃至+50℃的温度下,与式(IVa)的化合物反应,
其中式(IIIa)的化合物通过阮内镍氢化而获得,
[A2]将所得反应混合物加热至+70℃至+90℃的温度,
[A3]用合适的酸酸化反应混合物至pH值为0至3,
[A4]分离各相,并弃去水相,
[A5]加入水和合适的碱,将pH值调节为4至6,
[A6]分离各相,并弃去水相,
[A7]将反应混合物缓慢冷却至0℃至+10℃,
[A8]过滤反应混合物,用合适的溶剂洗涤滤饼,并干燥湿的滤饼,以得到式(I)的化合物或其盐。
非常特别优选地,方法[A]在步骤[A4]之后还包括其他步骤[A4a]和[A4b]
其中
[A4a]加入水和合适的酸,以将pH值调节为0到3,
[A4b]分离各相,并弃去水相。
用于步骤[A1]的合适的碱选自无机碱,例如碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁;或有机碱,例如三乙胺、N,N-二异丙基乙胺。用于步骤[A1]的优选的碱选自碳酸钠、碳酸钾、氢氧化钠、氢氧化钾和氢氧化钙。更优选的碱选自氢氧化钠、氢氧化钾和氢氧化钙。最优选的碱选自氢氧化钠和氢氧化钾。优选地,在步骤[A1]中,加入如本文所定义的碱,直到将反应溶液的pH值调节为pH 4至14,特别优选pH 6至9。
用于步骤[A1]的合适的溶剂选自醇,例如甲醇、乙醇、异丙醇、丙醇、正丁醇、异丁醇、叔戊醇、苯甲醇、1,3-丁二醇、1,4-丁二醇、2-丁氧基乙醇、环己醇、二乙二醇、二乙二醇甲醚、二丙二醇、二丙二醇甲醚、2-乙氧基乙醇、乙二醇、丙三醇、己醇、己二醇、异戊醇、异丁醇、2-甲氧基乙醇、1-辛醇、戊醇、丙二醇、四乙二醇、三乙二醇;醚,例如乙基丙基醚、甲基叔丁基醚、正丁基醚、苯甲醚、苯乙醚、环己基甲基醚、二甲醚、乙醚、二甲基乙二醇、二苯醚、二丙醚、二异丙醚、二正丁基醚、二异丁基醚、二异戊基醚、乙二醇二甲醚、异丙基乙基醚、四氢呋喃、甲基四氢呋喃、甲基环戊基醚、二噁烷、二氯二乙基醚、石油醚(petroleum ether)、粗汽油(ligroin)以及环氧乙烷和/或环氧丙烷的聚醚;烃,例如甲苯、二甲苯、乙苯;或其他溶剂,例如水或N,N-二甲基乙酰亚胺、N,N-二甲基甲酰胺、2-吡咯烷酮和N-甲基吡咯烷酮。优选的溶剂选自比例为10:1至1:10的水和烃,所述烃为例如甲苯、二甲苯和乙苯及其混合物。特别优选比例为1:1的水和甲苯的混合物。
优选地,在步骤[A2]中,将反应混合物加热至+70℃至+90℃的温度,保持30分钟至3小时。
更优选地,在步骤[A2]中,将反应混合物加热至+75℃至+90℃的温度,保持1小时至3小时。
更优选地,在步骤[A2]中,将反应混合物加热至+80℃至+85℃的温度,保持30分钟至3小时。
甚至更优选地,在步骤[A2]中,将反应混合物加热至+80℃至+85℃的温度,保持1小时至2小时。
用于步骤[A3]和[A4a]的合适的酸选自无机酸,例如气态氯化氢、盐酸(HCl)、硫酸(H2SO4)、磷酸(H3PO4);或有机酸,例如乙酸(CH3CO2H)、三氟乙酸(CF3CO2H)、柠檬酸、对甲苯磺酸、甲磺酸、三氟甲磺酸、甲酸。优选的酸选自盐酸(HCl)和硫酸(H2SO4)。优选地,在步骤[A3]和[A4a]中,将如本文所定义的酸加入反应混合物中,以将pH值调节至pH 0至4,非常优选调节至值为pH 0至3。
用于步骤[A5]的合适的碱选自无机碱,例如碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁;或有机碱,例如三乙胺、N,N-二异丙基乙胺。用于步骤[A5]的优选的碱选自碳酸钠、碳酸钾、氢氧化钠、氢氧化钾和氢氧化钙。更优选的碱选自氢氧化钠、氢氧化钾和氢氧化钙。最优选的碱选自氢氧化钠和氢氧化钾。优选地,在步骤[A5]中,加入如本文所定义的碱,直至将反应溶液的pH值调节至pH 4至7,特别优选pH 5至6。
由于其技术可行性,本发明的方法适于大规模生产。取代的2-(氨基甲基)吡啶衍生物是制备式(I)的吡啶基甲基苯甲酰胺衍生物的重要中间体。现有技术中记载的方法由于形成副产物、合成中使用的试剂和/或残余量的镍而不适于工业规模的生产。出人意料地,发现通过遵循本发明的方法,提供了一种经济的、技术上容易实行的方法,以使用通过阮内镍催化的氢化而获得的取代的2-(氨基甲基)吡啶衍生物来制备镍含量显著降低的式(I)的吡啶基甲基苯甲酰胺衍生物。因此,所获得的式(I)的吡啶基甲基苯甲酰胺衍生物适用于农产品。
方法和缩写
方法
方法1(HPLC):仪器:Agilent 1100;柱:Zorbax Eclipse XDB-C18 1.8μ,50mm×4.6mm;洗脱液A:1L水+1mL磷酸,洗脱液B:乙腈;梯度:0.0min 90%A→4.25min 5%A→6.0min 5%A→6.01min90%A;柱温:55℃;流速:2.0mL/min;UV检测:210nm。
方法2(原子吸收光谱法):石墨炉
缩写
HPLC 高压液相色谱法
wt.% 重量百分数
实施例
以下所示的实施例进一步说明本发明,而非限制本发明。
实施例1
在+20℃下,向597.8g 1-[-3-氯-5-(三氟甲基)吡啶-2-基]甲胺乙酸盐(2.2mol,纯度为77.5重量%,Ni含量为480ppm,根据WO 2004/046114制备)于1623g水和1623.5g甲苯中的溶液中,加入456.1g 2,6-二氯苯甲酰氯(2.175mol),并在60分钟内并行加入282.3g氢氧化钠水溶液(32重量%)。内部温度保持在+38℃和+43℃之间。反应是放热的。夹套温度保持在+30℃和+45℃之间。完全加入2,6-二氯苯甲酰氯后,使悬浮液在+40℃下再保持10分钟,然后在55分钟内将温度升至+80℃。将稠的悬浮液在+80℃下再搅拌15分钟。水相的pH值约为4.1。然后,在+80℃下,将109.5g盐酸(20重量%,0.651mol)加入悬浮液中,以将pH调节至<1。将所得两相溶液再搅拌5分钟。在+82℃下进行相分离之后,排出水相,并将176g水加入有机相中。水相的pH约为1.42。再加入9.2g盐酸(20重量%),以将pH调节至0.8。在82℃下进行相分离之后,将水相排出,向有机溶液中再加入176.5g水,并加入16.1g氢氧化钠水溶液(32重量%,0.129mol),以将pH调节至5-5.5。在+82℃下进行相分离之后,排出水相。将溶液在2小时内冷却至5℃并搅拌60分钟。结晶开始于约+60℃。最后,通过过滤分离产物,将湿滤饼在+5℃下用224g预冷的甲苯洗涤(置换洗涤),并将湿滤饼在+65℃下真空干燥。得到810.50g 2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲酰胺(99.7重量%),化学产率为95.71%。
Rt(方法1)=3.25min
镍含量(方法2):低于0.5ppm
Claims (11)
1.一种制备式(I)的取代的吡啶基甲基苯甲酰胺衍生物或其盐的方法,
其中
p为等于1、2、3或4的整数,
q为等于1、2、3或4的整数,
X独立地选自氢、卤素、(C1-C4)-烷基和(C1-C4)-卤代烷基,条件是至少一个X为卤素,
Y为卤素,
其特征在于,其包括以下步骤
[A1]在合适的溶剂中,在合适的碱的存在下,在0℃至+50℃的温度下,使式(III)的取代的2-(氨基甲基)吡啶基衍生物或其盐与式(IV)的化合物反应,
其中p和X如上定义,并且
其中式(III)的化合物通过阮内镍氢化而获得,
其中
q为等于1、2、3或4的整数,
Y为卤素,并且
L1为离去基团,
[A2]将所得反应混合物加热至+70℃至+90℃的温度,
[A3]用合适的酸酸化反应混合物至pH值为0至3,
[A4]分离各相,并弃去水相,
[A5]加入水和合适的碱,将pH值调节为4至6,
[A6]分离各相,并弃去水相,
[A7]将反应混合物缓慢冷却至0℃至+10℃
[A8]过滤反应混合物,用合适的溶剂洗涤滤饼,并干燥湿滤饼,以得到式(I)的化合物或其盐。
2.根据权利要求1所述的方法,其特征在于,方法[A]在步骤[A4]之后还包括其他步骤[A4a]和[A4b]
其中
[A4a]加入水和合适的酸,以将pH值调节为0至3,
[A4b]分离各相,并弃去水相。
3.根据权利要求1或2所述的方法,其特征在于,在步骤[A1]中,合适的溶剂选自比例为10:1至1:10的水和烃,所述烃为例如甲苯、二甲苯和乙苯及其混合物。
4.根据权利要求1至3中任一项所述的方法,其特征在于,在步骤[A1]中,合适的碱选自氢氧化钠和氢氧化钾。
5.根据权利要求1至4中任一项所述的方法,其特征在于,在步骤[A1]中,加入合适的碱直至将反应溶液的pH值调节为pH 6至9。
6.根据权利要求1至5中任一项所述的方法,其特征在于,在步骤[A3]中,合适的酸选自盐酸(HCl)和硫酸(H2SO4)。
7.根据权利要求2至5中任一项所述的方法,其特征在于,在步骤[A4a]中,合适的酸选自盐酸(HCl)和硫酸(H2SO4)。
8.根据权利要求1至7中任一项所述的方法,其特征在于,在步骤[A5]中,合适的碱选自氢氧化钠、氢氧化钾和氢氧化钙。
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