CN100413847C - 制备2-氨基甲基吡啶衍生物的方法 - Google Patents
制备2-氨基甲基吡啶衍生物的方法 Download PDFInfo
- Publication number
- CN100413847C CN100413847C CNB2004800110082A CN200480011008A CN100413847C CN 100413847 C CN100413847 C CN 100413847C CN B2004800110082 A CNB2004800110082 A CN B2004800110082A CN 200480011008 A CN200480011008 A CN 200480011008A CN 100413847 C CN100413847 C CN 100413847C
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- China
- Prior art keywords
- formula
- acid
- halogen atom
- sodium
- methyl
- Prior art date
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- Expired - Lifetime
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- 238000000034 method Methods 0.000 title claims abstract description 37
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical class NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title abstract description 7
- -1 2-substituted pyridine Chemical class 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- 239000010941 cobalt Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 3
- KBRRIEFTVXTTCR-UHFFFAOYSA-N 2-(nitromethyl)pyridine Chemical class [O-][N+](=O)CC1=CC=CC=N1 KBRRIEFTVXTTCR-UHFFFAOYSA-N 0.000 abstract 2
- RGDQRXPEZUNWHX-UHFFFAOYSA-N 3-methylpyridin-2-amine Chemical class CC1=CC=CN=C1N RGDQRXPEZUNWHX-UHFFFAOYSA-N 0.000 abstract 1
- 125000004971 nitroalkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000005695 dehalogenation reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 2
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical compound C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-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 (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- NALZTFARIYUCBY-UHFFFAOYSA-N 1-nitrobutane Chemical compound CCCC[N+]([O-])=O NALZTFARIYUCBY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- CCFGTKQIRWHYTB-UHFFFAOYSA-N 2-methyl-3-nitropyridine Chemical compound CC1=NC=CC=C1[N+]([O-])=O CCFGTKQIRWHYTB-UHFFFAOYSA-N 0.000 description 1
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical class [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 description 1
- KCDNYRPDKSGQCM-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1-(4-fluorophenyl)butan-1-one Chemical class C1=CC(F)=CC=C1C(=O)CCCN1CCC(C=2C=C(Cl)C=CC=2)(C(=O)N2CCCC2)CC1 KCDNYRPDKSGQCM-UHFFFAOYSA-N 0.000 description 1
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical group CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- MATQNAPNEIVYEJ-UHFFFAOYSA-N [N+](=O)([O-])CCC.CC1=C(C(=O)O)C=CC=C1C(=O)O Chemical compound [N+](=O)([O-])CCC.CC1=C(C(=O)O)C=CC=C1C(=O)O MATQNAPNEIVYEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
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- 229910052742 iron Inorganic materials 0.000 description 1
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- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 239000012074 organic phase Substances 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
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- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
本发明涉及一种制备式(I)2-氨基甲基吡啶衍生物的新颖方法，该方法包括：第一步，在碱存在下，使式(II)的2-取代吡啶衍生物与式(III)的硝基烷烃反应，形成式(IV)的2-硝基甲基吡啶衍生物，第二步，在催化剂和酸存在下使形成的2-硝基甲基吡啶衍生物氢化，式中的n、X、Y、R1、R2和A按照说明书中定义。
Description
本发明涉及一种制备2-氨基甲基吡啶衍生物的新颖方法，所述衍生物是可用来制备杀虫剂的中间体，所述方法是卤代吡啶衍生物与硝基甲烷缩合，形成的2-硝基甲基吡啶衍生物随后催化氢化。
硝基乙烷与电子接受体取代的卤代苯的缩合反应已经被公开(Tetrahedron Lett.1990，31，1093-1096)。脂族硝基的还原是普遍已知的反应(cf.J.Org.Chem.1993，58，2302：用钯/碳和氢在二乙醚中的还原，cf.Tetrahedron Lett.1989，30，731：用Raney镍和氢的还原反应，cf.J.Org.Chem.1986，51，4856：用硼氢化钠和氯化镍六水合物催化剂的还原反应，cf.J.Org.Chem.1990，55，4474：用氢化铝锂的还原反应，cf.Org.Syn.Coll.1943，2，617：用锡在盐酸中还原反应，cf.J Am.Chem.Soc.1951，73，1293：用铁在盐酸中还原反应，cf.WO 02/055476：在成形的Raney催化剂存在下，与氢或含氢气体混合物的还原反应)。
当硝基甲基吡啶被另外的卤原子取代时，存在的困难是要避免吡啶环在还原步骤中的氢解脱卤(P.N.Rylander，氢化方法，Best Synthetic Series，Academic Press，1985，第148页)。因此，一般认为上述方法在没有显著的进一步改进下，不能应用于卤素取代的硝基甲基-吡啶衍生物。
现在，本发明人发现了一种没有上述缺陷的制备2-氨基甲基吡啶衍生物的方法，观察到这种方法只有痕量的脱卤产物，因此能应用于工业规模生产。
因此，本发明涉及一种制备下面通式(I)的2-氨基甲基吡啶衍生物或其盐的方法，
其中，
n代表0、1、2或3，
X代表卤原子，
Y代表卤原子、卤代烷基、烷氧基羰基或烷基磺酰基，如果n为2或3，Y可以相同或不同，
R1代表氢、烷基、环烷基或环烷基甲基，
R2代表氢或烷基，
R1和R2还可以一起代表亚烷基，
该方法包括：第一步：在碱存在下使式(II)的2-取代吡啶衍生物与式(III)的硝基烷烃反应，
其中
n、X和Y按照上面定义，和
A代表卤原子、三氟甲基磺酰基或甲基磺酰基，或其他能作为带负电荷的离去基团的基团，
其中，
R1和R2按照上面定义，
形成式(IV)的2-硝基甲基吡啶衍生物
其中，
n、X、Y、R1和R2按照上面定义，
第二步：式(IV)的2-硝基甲基吡啶衍生物在催化剂和一种酸存在下进行氢化。
式(II)提供了对作为进行本发明方法第一步的原料的2-取代吡啶衍生物的一般定义。
对式(II)的2-取代吡啶衍生物的基团的优选定义如下。
n较好代表0、1或2，更好代表0或1，最好是1。
X较好代表氟，氯或溴，更好代表氟或氯，最好是氯。
X较好位于吡啶环的3-位，即在A基团的邻位。
Y较好代表氟、氯、溴、有1-13个选自氟、氯和溴的卤原子的C1-C6-卤代烷基、(C1-C6-烷氧基)羰基环C1-C6-烷基磺酰基，更好代表氟、氯、溴、有1-9个选自氟、氯和溴的卤原子C1-C4-卤代烷基、(C1-C4-烷氧基)羰基或C1-C4-烷基磺酰基，最好是氯、三氟甲基、三氯甲基、甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、甲基磺酰基或乙基磺酰基。
当n是1时，Y较好位于吡啶环5-位，即在A基团的对位。
A较好代表氟、氯、溴、三氟甲基磺酰基或甲基磺酰基，或其他能作为带负电荷离去基团的基团，更好代表氯、溴或三氟甲基磺酰基，最好是氯。
式(II)优选原料是2-取代吡啶衍生物，其中，n是1，X是氯，Y是C1-C4-卤代烷基，特别是三氟甲基，A是氯或三氟甲基磺酰基，特别是氯。
用作本发明方法原料的特别优选的式(II)2-取代吡啶衍生物是2，3-二氯-5-(三-氟甲基)吡啶。
式(II)的2-取代吡啶衍生物是已知的和/或可以采用已知方法制备。
式(III)提供对进行本发明方法第一步的原料的硝基烷烃的一般定义。
对式(III)硝基烷烃的基团的优选定义如下。
R1较好代表氢、C1-C6-烷基、C3-C8-环烷基或(C3-C8-环烷基)甲基，更好代表氢、C1-C6-烷基、C3-C6-环烷基或(C3-C6-环烷基)甲基，最好是氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、新己基、环丙基、环丁基、环戊基、环己基、环丙基甲基、环丁基甲基、环戊基甲基或环己基甲基。
R2较好代表氢或C1-C6-烷基，更好代表氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、新己基、最好代表氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基或异己基。
R1和R2还可以一起代表C2-C5-亚烷基，更好代表-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-。
式(III)的硝基烷烃是已知的化学物质。式(III)硝基烷烃的典型例子是：硝基甲烷、硝基乙烷、1-，2-硝基丙烷、2-硝基丙烷，1-，2-，3-，4-硝基丁烷，2-甲基-1-硝基丙烷，硝基环丙烷，硝基环丁烷，硝基环戊烷，硝基环己烷，硝基甲基环丙烷。这仅列举了式(III)硝基烷烃，并不构成对本发明范围的限制。
式(IV)提供了对作为进行本发明方法第二步原料的式(IV)2-硝基甲基吡啶衍生物的一般定义。
同样，对式(II)和(III)的较好，更好和最好的定义可应用于式(IV)的2-硝基甲基吡啶衍生物的基团。
式(IV)的2-硝基甲基吡啶衍生物是新颖化合物，也是本发明的一部分。
在所有情况下饱和或不饱和烃基如烷基和链烯基可以是直链或支链，只要可能，包括与杂原子的组合，如在烷氧基中。
本发明方法特别适合于制备2-氨基甲基-3-氯-5-三氟甲基吡啶，具体是，第一步：在叔丁醇钾、叔丁醇钠或氢氧化钾存在下，DMSO作为稀释剂，2，3-二氯-5-三氟甲基吡啶与硝基甲烷反应，形成3-氯-2-硝基甲基-5-三氟甲基吡啶，第二步：使用钯/碳作为催化剂，在盐酸中氢化，形成3-氯-2-氨基甲基-5-三氟甲基吡啶。
本发明的第一步在碱存在下进行。合适的碱是通常用于这类反应的任何无机碱和有机碱。较好的使用碱土金属或碱金属醇盐，如甲醇钠、乙醇钠、叔丁醇钾和异丁醇钠，碱金属和碱土金属氢氧化物，如氢氧化钠、氢氧化钙或氢氧化钾，碱金属碳酸盐或碳酸氢盐，如碳酸钠、碳酸钾、碳酸锂、碳酸铯、碳酸氢钾、碳酸氢钠，以及叔胺，如三甲胺，三乙胺，三丁胺，二异丙基乙胺，N，N-二甲基苯胺，吡啶，N-甲基哌啶，N，N-二甲基氨基吡啶，二氮杂二环辛烷(DABCO)，二氮杂二环-壬烯(DBN)或二氮杂二环十一碳烯(DBU)。更好是甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠、异丁醇钠、氢氧化钠和氢氧化钾，最好是叔丁醇钾、叔丁醇钠、氢氧化钠和氢氧化钾。
本发明方法第一步可任选在稀释剂存在下进行。合适的稀释剂是常用的惰性有机溶剂。优选使用任选卤代脂族烃、脂环族烃或芳族烃，如石油醚，己烷，庚烷，环己烷，甲基环己烷，苯，甲苯，二甲苯或萘烷；氯苯，二氯苯，二氯甲烷；醚，如二乙醚，二异丙基醚，甲基叔丁基醚，甲基叔戊基醚，二噁烷，四氢呋喃，1，2-二甲氧基-乙烷，1，2-二乙氧基乙烷或苯甲醚；醇，如甲醇，乙醇，叔丁醇和异丁醇；腈，如乙腈，丙腈，正丁腈或异丁腈或苄腈；酰胺，如N，N-二甲基甲酰胺，N，N-二甲基乙酰胺，N-甲基甲酰苯胺，N-甲基吡咯烷酮或六甲基磷酸三酰胺(hexamethylphosphoric triamide)；酯，如乙酸甲酯或乙酸乙酯；亚砜，如二甲基亚砜；或砜，如环丁砜。
本发明方法第一步中的反应温度可以在宽范围内变化。一般，在-20℃至+150℃，较好0℃至60℃，最好20℃至30℃进行该反应。
反应的第一步可以在大气压下进行，尽管也可以在减压或加压下进行。最好是大气压下进行该反应。
第一步的反应时间依据反应规模而不同，可以在1-48小时内变化，较好为3-24小时，最好是5-15小时。
实际进行所述方法的第一步时，例如，1mol式(II)的2-取代吡啶衍生物与1-10mol，较好1-5mol，更好1-3mol的式(III)烯基烷烃在1-10mol，较好1-5mol，更好1-3mol碱存在下反应。在某些情况还可以采用其他的比例。
本发明方法第二步在催化剂存在下进行。合适的催化剂有Raney镍，Raney钴，钯/碳，钯盐，铂和铂氧化物。优选Raney镍，Raney钴和钯/碳。具体的，钯/碳用量范围在式(IV)的2-硝基-甲基吡啶衍生物的0.0001-2当量。可以使用氯化铵作为助催化剂，其用量范围在0-10当量。为使脱卤化最小，加入催化剂抑制剂(如KBr)(cf.WO 02/16322)可能有利。
可以按照本领域技术人员已知的方法对催化剂再循环。特别是，通过过滤可以方便地再循环。
本发明方法的第二步可以在酸存在下进行。合适的酸可以是通常用于这类反应的任何无机酸和有机酸。优选使用无机酸，如盐酸、硫酸和磷酸；有机酸，如甲酸、乙酸、丙酸、三氟乙酸、三氯乙酸和甲磺酸。特别优选使用盐酸和乙酸。
本发明方法的第二步还可任选在稀释剂存在下进行。合适的稀释剂是常用的有机溶剂。优选使用任选卤代的脂族烃、脂环族烃或芳族烃，如石油醚，己烷，庚烷，环己烷，甲基环己烷，苯，甲苯，二甲苯或萘烷；氯苯，二氯苯，二氯甲烷；醚，如二乙醚，二异丙基醚，甲基叔丁基醚，甲基叔戊基醚，二噁烷，四氢呋喃，1，2-二甲氧基乙烷，1，2-二乙氧基乙烷或苯甲醚；醇，如甲醇，乙醇，叔丁醇和异丁醇；酰胺，如N，N-二甲基甲酰胺，N，N-二甲基乙酰胺，N-甲基甲酰苯胺，N-甲基吡咯烷酮或六甲基磷酸三酰胺；酯，如乙酸甲酯或乙酸乙酯；有机酸如乙酸。
本发明方法第二步的反应温度可以在宽范围内变化。反应一般在-20℃至+150℃，较好0℃至60℃，最好在20℃至30℃进行。
该第二步可在0.5至200bar，较好2至50bar，最好3至10bar氢压下进行。第二步的反应时间依据反应规模而不同，可以在1-48小时范围，较好为3-26小时。
实际进行该反应第二步时，例如，是1mol式(IV)的2-硝基甲基吡啶衍生物在催化剂存在下以及0-10mol，较好1-5mol，更好2-3mol的酸存在下进行。
下面，参照实施例说明本发明的方法。
制备例
实施例1(3-氯-2-硝基甲基-5-三氟甲基吡啶)
将叔丁醇钾(20.2g，0.18mol，2eq.)与90ml无水二甲基亚砜一起放入250ml三口烧瓶中。在干氩气气氛下，机械搅拌下缓慢加入硝基甲烷(11g，0.18mol，2eq.)，同时用冰浴冷却。在20℃继续搅拌反应混合物15分钟。然后，在17℃，5分钟内加入2，3-二氯-5-三氟甲基吡啶(19.44g，0.09mol，1eq.)。温度先下降到13℃，而在添加结束后，观察到放热反应达到27℃。将混合物冷却至室温，再继续搅拌14小时。
将深棕色粗产物倒入150ml水中，随后用乙酸乙酯萃取三次，每次50ml。合并后的有机层每次用30ml水洗涤，共三次，随后在无水硫酸钠上干燥。过滤后，在20℃和150mbar减压下除去溶剂。
产量：22.8g 3-氯-2-硝基甲基-5-三氟甲基吡啶(95.7％理论产率，90.9％纯度)
1H NMR(d6-DMSO)：δ＝6.21(s，2H)，8.68(d，1H)，9.05(dd，1H)ppm。
MS(LC/MS-偶合)：m/z(％)＝243(36)和241(100)每个[M++H]。
实施例2(3-氯-2-硝基甲基-5-三氟甲基吡啶，PyMN)
将粉末氢氧化钾(9.35g，0.15mol，3eq.)与70ml无水DMSO一起放入250ml三口烧瓶中，在干氩气气氛下，机械搅拌下在30分钟内，加入溶解在30ml无水DMSO中的硝基甲烷(6.1g，0.1mol，2eq)，同时用冰浴冷却，保持温度为20℃。在20℃再继续搅拌反应混合物15分钟。然后，一份加入2，3-二氯-5-三氟甲基吡啶(10.80g，0.05mol，1eq.)，没有吸热或放热反应。混合物加热至50℃，在此温度搅拌3小时，然后冷却至室温。
将深棕色粗产物倒入500ml水中，加入稀盐酸进行酸化，随后用乙酸乙酯萃取三次，每次50ml。合并后的有机层每次用30ml水洗涤，共三次，随后在无水硫酸钠上干燥。过滤后，在20℃和150mbar减压下除去溶剂。
产量：9.72g 3-氯-2-硝基甲基-5-三氟甲基吡啶(73.9％理论产率，91.4％纯度)
实施例3(盐酸3-氯-2-氨基甲基-5-三氟甲基吡啶)
制备7.69g(0.211mol，2eq.)盐酸在无水甲醇的溶液，方法如下：用适量甲醇稀释30％甲醇(methanolic)HCl。将3-氯-2-硝基甲基-5-三氟甲基吡啶(25.9g，0.106mol，1eq.)和5.50g 5％钯/碳与上面制得的甲醇HCl一起放入哈斯特洛伊耐蚀镍基合金高压釜，在室温和5bar氢压下反应26小时。
调节压力至1bar后，过滤除去催化剂，用少量甲醇洗涤后，合并全部有机相，于30℃和150mbar减压下除去溶剂。
获得的粗产物悬浮于二氯甲烷进行纯化。过滤并用二氯甲烷洗涤后，浅灰色结晶在五氧化磷上干燥。
产量：24.13g盐酸3-氯-2-氨基甲基-5-三氟甲基吡啶(92.5％理论产率，99.9％纯度
1H NMR(d6-DMSO)：δ＝4.37(d，2H)，8.61(d，1H)，8.83(s宽，3H)，9.03(d，1H)ppm。
MS(GC/MS-偶合)：m/z(％)＝212(13)和210(38)每个[M+]，184(24)和182(79)，30(100)。
Claims (9)
1. 一种制备通式(I)的2-氨基甲基吡啶衍生物或其盐的方法，
其中，
n代表1，
X代表卤原子，且处于3-位
Y代表卤原子，或有1-13个选自氟、氯和溴的卤素原子的C1-C6卤代烷基，所述的Y处于5-位，
R1代表氢或C1-C6烷基，
R2代表氢或C1-C6烷基，或者
R1和R2还可以一起代表C2-C5亚烷基，
所述方法包括：第一步：在碱存在下，使式(II)的2-取代吡啶衍生物与式(III)的硝基烷烃反应，
其中，
n，X和Y按照上面定义，
A代表卤原子、三氟甲基磺酰基或甲基磺酰基，
其中，
R1和R2按照上面定义，
形成式(IV)的2-硝基甲基吡啶衍生物，
其中，
n，X，Y，R1和R2按照上面定义，
第二步：在催化剂和酸存在下，使式(IV)的2-硝基甲基吡啶衍生物氢化。
2. 如权利要求1所述的方法，其特征在于，第一步中，使用甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠、异丁醇钠、氢氧化钠或氢氧化钾作为碱.
3. 如权利要求2所述的方法，其特征在于，第一步中，使用叔丁醇钾、叔丁醇钠、氢氧化钠或氢氧化钾作为碱。
4. 如权利要求1-3任一所述的方法，其特征在于，第二步中，使用Raney镍，Raney钴或钯/碳。
5. 如权利要求4所述的方法，其特征在于，在第二步中，钯/碳作为催化剂。
6. 如权利要求1-5中任一项所述的方法，其特征在于，在第二步中，使用盐酸、硫酸、磷酸、甲酸、乙酸、丙酸、三氟乙酸、三氯乙酸或甲磺酸。
7. 如权利要求6所述的方法，其特征在于，在第二步中，使用盐酸或乙酸作为酸。
8. 式(IV)的2-硝基甲基吡啶衍生物，
其中
n代表1，
X代表卤原子，且处于3-位，
Y代表卤原子，或有1-13个选自氟、氯和溴的卤素原子的C1-C6卤代烷基，所述的Y在5-位上，
R1代表氢或C1-C6烷基，
R2代表氢或C1-C6烷基，或者
R1和R2还可以一起代表C2-C5亚烷基。
9. 一种制备如权利要求8所述的式(IV)2-硝基甲基吡啶衍生物的方法，该方法包括在碱存在下，使式(II)的2-取代吡啶衍生物与式(III)硝基烷烃反应，
其中，
n，X和Y按照权利要求8所述定义
A代表卤原子、三氟甲基磺酰基、甲基磺酰基，
其中，
R1和R2按照权利要求8所述定义。
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| CN106220555B (zh) * | 2016-07-29 | 2019-06-21 | 天津市均凯化工科技有限公司 | 一种制备2-氨甲基-3-氯-5-三氟甲基吡啶的方法 |
| TWI650318B (zh) * | 2017-10-30 | 2019-02-11 | 財團法人工業技術研究院 | 以結晶法純化２，５－呋喃二甲酸的粗產物之方法與聚酯之形成方法 |
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| ZA885069B (en) * | 1987-07-24 | 1989-03-29 | Fujisawa Pharmaceutical Co | Sustained-release percutaneous preparations |
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| US7608720B2 (en) | 2009-10-27 |
| CN1777588A (zh) | 2006-05-24 |
| KR20060005396A (ko) | 2006-01-17 |
| TWI359139B (en) | 2012-03-01 |
| KR101213005B1 (ko) | 2012-12-18 |
| DE602004005175T2 (de) | 2007-12-20 |
| ATE356116T1 (de) | 2007-03-15 |
| DE602004005175D1 (de) | 2007-04-19 |
| EP1620404B1 (en) | 2007-03-07 |
| KR101130601B1 (ko) | 2012-04-02 |
| US20060235229A1 (en) | 2006-10-19 |
| GB0309631D0 (en) | 2003-06-04 |
| PL1620404T3 (pl) | 2007-07-31 |
| DK1620404T3 (da) | 2007-04-02 |
| IL170657A (en) | 2011-02-28 |
| WO2004096772A1 (en) | 2004-11-11 |
| JP4718446B2 (ja) | 2011-07-06 |
| EP1620404A1 (en) | 2006-02-01 |
| BRPI0409517A (pt) | 2006-04-18 |
| JP2006524665A (ja) | 2006-11-02 |
| ES2279383T3 (es) | 2007-08-16 |
| TW200502220A (en) | 2005-01-16 |
| KR20110133063A (ko) | 2011-12-09 |
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