TWI806930B - 用於製備氟比來之方法 - Google Patents
用於製備氟比來之方法 Download PDFInfo
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- TWI806930B TWI806930B TW107141169A TW107141169A TWI806930B TW I806930 B TWI806930 B TW I806930B TW 107141169 A TW107141169 A TW 107141169A TW 107141169 A TW107141169 A TW 107141169A TW I806930 B TWI806930 B TW I806930B
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- halogen
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 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 abstract description 6
- 239000005782 Fluopicolide Substances 0.000 title abstract 2
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical class NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 16
- 229910052759 nickel Inorganic materials 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 239000002904 solvent Substances 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
- 150000003839 salts Chemical class 0.000 claims description 7
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000012071 phase 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
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 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
- SZKNZEDOFVRAFQ-UHFFFAOYSA-N acetic acid;[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanamine Chemical compound CC(O)=O.NCC1=NC=C(C(F)(F)F)C=C1Cl SZKNZEDOFVRAFQ-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract 1
- 229910000564 Raney nickel Inorganic materials 0.000 abstract 1
- -1 2-methylpropyl (secondary butyl) Chemical group 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 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
- 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 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
- 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
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 125000005843 halogen group Chemical group 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
- 235000011007 phosphoric acid Nutrition 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
- 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 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
- 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
- 239000012065 filter cake Substances 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 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
- 238000010979 pH adjustment Methods 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 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 class OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 0.000 description 2
- 235000011149 sulphuric acid Nutrition 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
- 125000006526 (C1-C2) alkyl group Chemical group 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
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-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
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- FUPKVFJSGNZICR-UHFFFAOYSA-N 3-chloro-5-(trifluoromethyl)pyridine-2-carbonitrile Chemical compound FC(F)(F)C1=CN=C(C#N)C(Cl)=C1 FUPKVFJSGNZICR-UHFFFAOYSA-N 0.000 description 1
- 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
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- AQZGPSLYZOOYQP-UHFFFAOYSA-N Diisoamyl ether Chemical compound CC(C)CCOCCC(C)C AQZGPSLYZOOYQP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N Tetraethylene glycol, Natural products OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000009904 heterogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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Abstract
本發明係關於一種用於從藉由雷氏鎳(Raney-Nickel)氫化所得到的經取代的2-(胺基甲基)吡啶衍生物製備式(I)之經取代的吡啶基甲基苯甲醯胺衍生物，特別是2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲醯胺(氟比來)，的改良方法。
Description
本發明係關於一種用於從藉由雷氏鎳氫化所得到的經取代的2-(胺基甲基)吡啶衍生物製備式(I)之經取代的吡啶基甲基苯甲醯胺衍生物，特別是2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲醯胺(氟比來)，的改良方法。
式(I)之經取代的吡啶基甲基苯甲醯胺衍生物
其中，p是等於1、2、3或4之整數，q是等於1、2、3或4之整數，X是獨立地選自由氫、鹵素、(C1-C4)-烷基及(C1-C4)-鹵烷基所組成之群，條件是至少一個X是鹵素，Y是鹵素，其對植物致病真菌具有高度活性。式(I)之化合物是揭示在EP 1056723 B1中。
經取代的2-(胺基甲基)吡啶衍生物，諸如特別是3-氯-2-氰基-5-三氟甲基吡啶，是用於製備根據如下所示的式(Ia)的一種商業化供應的殺真菌劑氟比來(2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲醯胺)的重要中間體
經取代的2-(胺基甲基)吡啶衍生物之製備於先前技術中是已知的。WO 99/42447及WO 2004/65359揭示經由經取代的亞胺衍生物形成經取代的吡啶基甲基苯甲醯胺衍生物。此方法涉及數個步驟且因此不是非常有效率。WO 2002/016322揭示在鈀炭存在下，藉由氫化對應的經取代2-氰基吡啶衍生物製備經取代2-(胺基甲基)吡啶衍生物。但是，該方法具有幾個缺點，諸如氫化步驟的產率低、脫鹵化副產物的形成、2-(胺基甲基)吡啶衍生物的分離及分離物質的穩定性問題。WO 2004/046114揭示在醋酸中在雷氏鎳存在下催化氫化經取代的2-氰基吡啶衍生物成為對應的2-(胺基甲基)吡啶衍生物。通常，腈的催化氫化在文獻中是眾所周知的，並且可以用不同的鎳催化劑進行(Nishimura在"Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis"中，pp.259-285,John Wiley and Sons,New York,2001)。還已知腈類催化氫化成為所欲的一級胺類通常伴隨著大量的二級及三級胺類的形成，這些二級及三級胺類污染所欲的一級胺類並使分離非常複雜、昂貴且低效，因此不適合於在工業規模上使用。令人驚訝的是，在WO 2004/046114中揭示的方法不會導致形成不需要的副產物，因此是在WO 99/4247、WO 2004/6535及WO 2002/016322中揭示的方法的良好替代方案。然而，如WO 2004/046114中所述，在雷氏鎳存在下經由氫化還原經取代的2-氰基吡啶衍生物具有巨大的缺點，即所得的2-(胺基甲基)吡 啶衍生物以及隨後的經取代的吡啶基甲基苯甲醯胺衍生物由於所謂的鎳浸出(nickel-leaching)被鎳污染至農產品所不能接受的程度。因此，所揭示的現有技術方法不太適合大規模生產。WO 99/42447中揭示用於形成式(I)之經取代的吡啶基甲基苯甲醯胺衍生物的方法不適合大規模生產。
因此，本發明的一個目的是提供一種新穎的、改進的、技術上可行的、更經濟和環境可行的方法，合適用於從藉由雷氏鎳氫化所得到的經取代2-(胺基甲基)吡啶衍生物以工業化規模製備明顯降低鎳含量的經取代吡啶基甲基苯甲醯胺衍生物。
如下文中詳細描述的，本發明的新方法提供一種經濟、技術上容易實現的方法，該方法解決了現有技術中描述的上述方法的問題，因此合適用於從藉由雷氏鎳氫化所得到的經取代2-(胺基甲基)吡啶衍生物以工業化規模製備明顯降低鎳含量的經取代吡啶基甲基苯甲醯胺衍生物。
本發明的目的是一種方法[A]用於製備式(I)之經取代吡啶基甲基苯甲醯胺衍生物或其鹽類，
其中，p是等於1、2、3或4之整數，q是等於1、2、3或4之整數，X是獨立地選自由氫、鹵素、(C1-C4)-烷基及(C1-C4)-鹵烷基所組成之群，條件是至少一個X是鹵素， Y是鹵素，其特徵在於其包含以下步驟，[A1]在合適的溶劑中，在合適的鹼存在下，在0℃至+50℃的溫度下，使根據式(III)之經取代2-(胺基甲基)吡啶衍生物或其鹽類
其中p及X是根據上述的定義，且其中式(III)化合物是經由雷氏鎳氫化所得，與式(IV)化合物反應
其中q是等於1、2、3或4之整數，Y是鹵素，且L1是一個脫離基，[A2]將所得的反應混合物加熱至+70℃至+90℃的溫度，[A3]用合適的酸酸化反應混合物至0至3的pH值，[A4]分離各相並丟棄水相，[A5]加入水及合適的鹼以調節4到6的pH值，[A6]分離各相並丟棄水相，[A7]將反應混合物緩慢冷卻至0℃至+10℃， [A8]過濾反應混合物，用合適的溶劑洗滌濾餅並乾燥濕濾餅以產生式(I)化合物或其鹽類。
在另一個具體實例中，方法[A]在步驟[A4]之後包含進一步的步驟[A4a]和[A4b]，其中[A4a]加入水及合適的酸以調節0到3的pH值，[A4b]分離各相並丟棄水相。
除非另有說明，以下定義適用於本說明書及申請專利範圍中使用的取代基及殘基。
根據式(I)之化合物的相對應鹽較佳係硫酸氫鹽、硫酸鹽、硫酸氫鹽-硫酸鹽混合物、鹽酸鹽、磷酸鹽、甲酸鹽或乙酸鹽。
根據式(III)之化合物的相對應鹽較佳係硫酸氫鹽、硫酸鹽、硫酸氫鹽-硫酸鹽混合物、鹽酸鹽、磷酸鹽、甲酸鹽或乙酸鹽。尤佳係乙酸鹽。
在整個發明中，術語當量是指莫耳當量。
烷基表示具有1至4個碳原子的直鏈或支鏈飽和烴基。非限制性實例包括甲基、乙基、丙基、1-甲基乙基(異丙基)、正丁基、1-甲基丙基(異丁基)、2-甲基丙基(二級丁基)、1,1-二甲基乙基(三級丁基)。較佳的(C1-C2)-烷基是表示具有1或2個碳原子的直鏈飽和烴基，諸如甲基或乙基。
鹵烷基通常表示具有1至4個碳原子的烷基，其中1個至所有的氫原子被鹵素原子取代。非限制性實例包括氯甲基、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。較佳係二氟甲基、三氟甲基、二氯甲基、三氯甲基。
X較佳是獨立地選自由氟、氯、溴、甲基、乙基、具有1至5個獨立地選自由氟及氯所組成之群的鹵素原子的(C1-C2)-鹵烷基所組成之群。
X更佳是獨立地選自由氟、氯、甲基、乙基、或具有1至5個獨立地選自由氟及氯所組成之群的鹵素原子的(C1-C2)-鹵烷基所組成之群。
X尤佳是選自由氟、氯、二氟甲基、三氟甲基、二氯甲基及三氯甲基所組成之群。
X特佳是獨立地選自由氯及三氟甲基所組成之群。
尤佳地，2-吡啶基部分在3號及5號位置被X取代。
特佳地，根據式(III)的化合物是根據式(IIIa)的1-[3-氯-5-(三氟甲基)吡啶-2-基甲胺-乙酸鹽
Y較佳是獨立地選自由氟、氯及溴所組成之群。
Y更佳是獨立地選自由氟及氯所組成之群。
Y尤佳是氯。
更佳地，苯甲醯基部分是在2號位置及6號位置被X取代。
尤佳地，根據式(IV)的化合物是根據式(IVa)的2,6-二氯苯甲醯氯
p較佳是等於1、2或3的整數。
p更佳是等於1或2的整數。
p尤佳是等於2的整數。
q較佳是等於1、2或3的整數。
q更佳是等於1或2的整數。
q尤佳是等於2的整數。
脫離基L1較佳是鹵素。
脫離基L1更佳是選自由氯、溴及碘所組成之群。
脫離基L1尤佳是氯。
特佳地，根據式(I)的化合物是根據式(Ia)的氟比來
尤佳地，本發明之目的是一種用於製備式(Ia)之經取代的吡啶基甲基苯甲醯胺之方法[A]
其特徵在於其包含以下步驟[A1]在合適的溶劑中，在合適的鹼存在下，在0℃至+50℃的溫度下，使根據式(IIIa)之經取代2-(胺基甲基)吡啶基衍生物
其中式(IIIa)化合物是經由雷氏鎳氫化所得，與式(IVa)的化合物反應
[A2]將所得的反應混合物加熱至+70℃至+90℃的溫度，[A3]用合適的酸酸化反應混合物至0至3的pH值，[A4]分離各相並丟棄水相，[A5]加水及適量鹼以調節4至6之pH值，[A6]分離各相並丟棄水相，[A7]將反應混合物緩慢冷卻至0℃至+10℃，[A8]過濾反應混合物，用合適的溶劑洗滌濾餅並乾燥濕濾餅以產生式(I)化合物或其鹽。
特佳地，方法[A]在步驟[A4]之後包含進一步的步驟[A4a]及[A4b]，其中，[A4a]加入水及合適的酸以調節0至3之pH值，[A4b]分離各相並丟棄水相。
步驟[A1]的合適的鹼是選自無機鹼，諸如碳酸鈉、碳酸氫鈉、碳酸鉀、碳酸氫鉀、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂或有機鹼，諸如三乙胺、N,N-二異丙基乙胺。步驟[A1]的較佳地鹼是選自碳酸鈉、碳酸鉀、氫氧化鈉、氫氧化鉀及氫氧化鈣。更佳的鹼是選自氫氧化鈉、氫氧化 鉀及氫氧化鈣。最佳的鹼是選自氫氧化鈉及氫氧化鉀。較佳地，在步驟[A1]中，加入如本文所定義的鹼，直至達成反應溶液的pH 4至14、尤佳pH 6至9之pH值調節。
步驟[A1]的合適的溶劑是選自醇，諸如甲醇、乙醇、異丙醇、丙醇、正丁醇、異丁醇、第三戊醇、苯甲醇、1,3-丁二醇、1,4-丁二醇、2-丁氧基乙醇、環己醇、二甘醇、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、甘油、己醇、己二醇、異戊醇、異丁醇，2-甲氧基乙醇、1-辛醇、戊醇、丙二醇、四甘醇、三甘醇；選自醚，諸如乙基丙基醚、甲基三級丁基醚、正丁基醚、苯甲醚、苯乙醚、環己基甲基醚、二甲醚、二乙醚、二甲基乙二醇、二苯醚、二丙醚、二異丙醚、二正丁醚、二異丁醚、二異戊醚、乙二醇二甲醚、異丙基乙基醚、四氫呋喃、甲基四氫呋喃、甲基環戊基醚、二
烷、二氯二乙基醚、石油醚、揮發油及環氧乙烷及/或環氧丙烷的聚醚；選自碳氫化合物，諸如甲苯、二甲苯、乙苯，或選自其他溶劑，諸如水或N,N-二甲基乙醯胺、N,N-二甲基甲醯胺、2-吡咯烷酮及N-甲基吡咯烷酮。較佳的溶劑是選自水和烴類，諸如甲苯、二甲苯和乙苯，及比例為10：1至1：10的其混合物。尤佳係水和甲苯的比例為1：1的混合物。
較佳地，將步驟[A2]中的反應混合物加熱至+70℃至+90℃的溫度達30分鐘至3小時。
更佳地，將步驟[A2]中的反應混合物加熱至+75℃至+90℃的溫度達1小時至3小時。
更佳地，將步驟[A2]中的反應混合物加熱至+80℃至+85℃的溫度達30分鐘至3小時。
甚至更佳地，將步驟[A2]中的反應混合物加熱至+80℃至+85℃的溫度達1小時至2小時。
步驟[A3]和[A4a]的合適的酸是選自無機酸，諸如氣態氯化氫、鹽酸(HCl)、硫酸(H2SO4)、磷酸(H3PO4)或有機酸，諸如乙酸(CH3CO2H)、三氟乙酸(CF3CO2H)、檸檬酸、對甲苯磺酸、甲磺酸、三氟甲磺酸、甲酸。較佳的酸是選自鹽酸(HCl)和硫酸(H2SO4)。較佳地，在步驟[A3]和[A4a]中，將如本文所定義的酸加入到反應混合物中以將pH值調節至pH 0至4，特佳係pH 0至3。
步驟[A5]的合適的鹼是選自無機鹼，諸如碳酸鈉、碳酸氫鈉、碳酸鉀、碳酸氫鉀、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂或有機鹼，諸如三乙胺、N,N-二異丙基乙胺。步驟[A5]的較佳的鹼是選自碳酸鈉、碳酸鉀、氫氧化鈉、氫氧化鉀和氫氧化鈣。更佳的鹼是選自氫氧化鈉、氫氧化鉀和氫氧化鈣。最佳的鹼是選自氫氧化鈉和氫氧化鉀。較佳地，在步驟[A5]中，加入如本文所定義的鹼，直到達成反應溶液的pH 4至7、尤佳pH 5至6之pH值調節。
由於其技術可行性，根據本發明的方法適合於大規模生產。經取代的2-(胺基甲基)吡啶衍生物是製備式(I)的吡啶基甲基苯甲醯胺衍生物的重要中間體。由於副產物的形成、合成中使用的試劑和/或鎳的殘留量，現有技術中描述的方法不適合工業規模生產。令人驚奇的是，已經發現藉由本發明的方法，提供經濟、技術上容易實施的方法，以使用經由雷氏鎳催化氫化獲得的經取代2-(胺基甲基)吡啶衍生物來製備式(I)的吡啶基甲基苯甲醯胺衍生物，可以顯著降低鎳含量。因此，所得的式(I)的吡啶基甲基苯甲醯胺衍生物適用於農產品。
方法
方法1(HPLC)：儀器：Agilent 1100；管柱：Zorbax Eclipse XDB-C18 1.8μ，50mm x 4.6mm；沖提液A：1L水+1mL磷酸，沖提液B：乙腈；梯度：0.0min 90%A→4.25min 5% A→6.0min 5% A→6.01min 90% A；管柱溫度：55℃；流速：2.0ml/min；UV檢測：210nm。
方法2(原子吸收光譜法)：石墨爐
縮寫
HPLC：高壓液相層析法
wt%：重量百分比
以下所示的實施例是進一步說明本發明而不是限制本發明。
在597.8g的1-[3-氯-5-(三氟甲基)吡啶-2-基]甲胺-乙酸鹽(2.2mol，77.5wt%純度，鎳含量480ppm，根據WO 2004/046114製備)在1623g水和1623.5g甲苯的溶液中，在+20℃下加入456.1g的2,6-二氯苯甲醯氯(2.175mol)，並在60分鐘內平行加入282.3g的氫氧化鈉水溶液(32wt%)。內部溫度保持在+38℃至+43℃之間。反應放熱。夾套溫度保持在+30℃至+45℃之間。在完全加入2,6-二氯苯甲醯氯後，使懸浮液在+40℃下再進行10分鐘，然後在55分鐘內將溫度升至+80℃。將濃稠懸浮液在+80℃下再攪拌15分鐘。水相的pH值約為4.1。然後在+80℃下將109.5g的鹽酸(20wt%，0.651mol)加入到懸浮液中將pH調節至<1。將所得的雙相溶液再攪拌5分鐘。在+82℃下相分離後，排出水相，在有機相中加入176g的水。水相的pH約為1.42。再加入9.2g鹽酸(20wt%)將pH調節至0.8。在82℃下相分離後，排出水相，並在有機溶液中再加入176.5g的水，並加入16.1g氫氧化鈉水溶液(32wt%，0.129mol)將pH調節至5-5.5。在+82℃下相分離後，排出水相。將溶液在2 小時內冷卻至5℃並攪拌60分鐘。結晶於約+60℃下開始。最後藉由過濾分離產物，並在+5℃下用224g的預冷甲苯(置換洗滌)洗滌濕濾餅，並將濕濾餅在+65℃下真空乾燥。得到810.50g的2,6-二氯-N-{[3-氯-5-(三氟甲基)-2-吡啶基]甲基}苯甲醯胺(99.7wt%)，化學產率95.71%。
Rt(方法1)=3.25min
鎳含量(方法2)：低於0.5ppm
Claims (11)
- 一種用於製備式(I)之經取代吡啶基甲基苯甲醯胺衍生物或其鹽類的方法，
- 根據申請專利範圍第1項之方法，其特徵在於方法[A]在步驟[A4]之後包含進一步的步驟[A4a]和[A4b]，其中[A4a]加入水及合適的酸以調節0到3的pH值，[A4b]分離各相並丟棄水相。
- 根據申請專利範圍第1或2項之方法，其特徵在於在步驟[A1]中的合適的溶劑是選自水和烴類，諸如甲苯、二甲苯和乙苯，及比例為10：1至1：10的其混合物。
- 根據申請專利範圍第1或2項之方法，其特徵在於在步驟[A1]中的合適的鹼是選自氫氧化鈉及氫氧化鉀。
- 根據申請專利範圍第1或2項之方法，其特徵在於在步驟[A1]中的合適的鹼是添加直至達成反應溶液的pH 6至9之pH值的調整。
- 根據申請專利範圍第1或2項之方法，其特徵在於在步驟[A3] 中的合適的酸是選自鹽酸(HCl)和硫酸(H2SO4)。
- 根據申請專利範圍第2項之方法，其特徵在於在步驟[A4a]中的合適的酸是選自鹽酸(HCl)和硫酸(H2SO4)。
- 根據申請專利範圍第1或2項之方法，其特徵在於在步驟[A5]中的合適的鹼是選自氫氧化鈉、氫氧化鉀及氫氧化鈣。
- 根據申請專利範圍第1或2項之方法，其特徵在於該根據式(I)的化合物是根據式(Ia)的氟比來
- 根據申請專利範圍第1或2項之方法，其特徵在於該根據式(III)的化合物是根據式(IIIa)的1-[3-氯-5-(三氟甲基)吡啶-2-基]甲胺-乙酸鹽
- 根據申請專利範圍第1或2項之方法，其特徵在於該根據式(IV)的化合物是根據式(IVa)的2,6-二氯苯甲醯氯
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