CN1085662C - 制备氯甲基吡啶类化合物的方法 - Google Patents
制备氯甲基吡啶类化合物的方法 Download PDFInfo
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- CN1085662C CN1085662C CN94108119A CN94108119A CN1085662C CN 1085662 C CN1085662 C CN 1085662C CN 94108119 A CN94108119 A CN 94108119A CN 94108119 A CN94108119 A CN 94108119A CN 1085662 C CN1085662 C CN 1085662C
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- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical class ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 title claims abstract 3
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 26
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical class NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- VPCDQGACGWYTMC-UHFFFAOYSA-N nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 claims description 7
- 235000019392 nitrosyl chloride Nutrition 0.000 claims description 7
- SKCNYHLTRZIINA-UHFFFAOYSA-N 2-chloro-5-(chloromethyl)pyridine Chemical compound ClCC1=CC=C(Cl)N=C1 SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 claims description 6
- 239000004157 Nitrosyl chloride Substances 0.000 claims description 6
- XPARFBOWIYMLMY-UHFFFAOYSA-N (6-chloropyridin-3-yl)methanamine Chemical compound NCC1=CC=C(Cl)N=C1 XPARFBOWIYMLMY-UHFFFAOYSA-N 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 4
- 239000003085 diluting agent Substances 0.000 abstract description 2
- -1 chloromethyl pyridine compound Chemical class 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000006193 diazotization reaction Methods 0.000 description 7
- 230000009935 nitrosation Effects 0.000 description 7
- 238000007034 nitrosation reaction Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-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
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- PHBVTMQLXNCAQO-UHFFFAOYSA-N 5-(aminomethyl)pyridin-2-amine Chemical compound NCC1=CC=C(N)N=C1 PHBVTMQLXNCAQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Chemical group 0.000 description 2
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical compound CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- LZDSILRDTDCIQT-UHFFFAOYSA-N dinitrogen trioxide Chemical compound [O-][N+](=O)N=O LZDSILRDTDCIQT-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- CNQCWYFDIQSALX-UHFFFAOYSA-N 3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1 CNQCWYFDIQSALX-UHFFFAOYSA-N 0.000 description 1
- RXQNKKRGJJRMKD-UHFFFAOYSA-N 5-bromo-2-methylaniline Chemical compound CC1=CC=C(Br)C=C1N RXQNKKRGJJRMKD-UHFFFAOYSA-N 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical compound CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 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
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- WDSYFPPDMKLHFL-UHFFFAOYSA-M azanium benzyl(triethyl)azanium dihydroxide Chemical compound [OH-].[NH4+].[OH-].C(C1=CC=CC=C1)[N+](CC)(CC)CC WDSYFPPDMKLHFL-UHFFFAOYSA-M 0.000 description 1
- QSRFYFHZPSGRQX-UHFFFAOYSA-N benzyl(tributyl)azanium Chemical compound CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 QSRFYFHZPSGRQX-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- BEVHTMLFDWFAQF-UHFFFAOYSA-N butyl(triphenyl)phosphanium Chemical class C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCC)C1=CC=CC=C1 BEVHTMLFDWFAQF-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960000800 cetrimonium bromide Drugs 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- MDQRDWAGHRLBPA-UHFFFAOYSA-N fluoroamine Chemical compound FN MDQRDWAGHRLBPA-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- NZMAJUHVSZBJHL-UHFFFAOYSA-N n,n-dibutylformamide Chemical compound CCCCN(C=O)CCCC NZMAJUHVSZBJHL-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical class OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- KAOQVXHBVNKNHA-UHFFFAOYSA-N propyl nitrite Chemical compound CCCON=O KAOQVXHBVNKNHA-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
Abstract
本发明涉及制备通式(I)的氯甲基吡啶类化合物(其中n代表数字0、1、2或3，和×代表卤素)的一种新方法，即将通式(II)的氨甲基吡啶类化合物与亚硝基化剂或重氮化剂在稀释剂存在下及任选在氯化氢的存在下，在温度为-20℃至+50℃之间进行反应，然后按照常规方法进行处理。
Description
本发明涉及制备氯甲基吡啶类化合物的一种新方法。
已知氯甲基吡啶类化合物可由羟甲基吡啶类化合物与亚硫酰氯反应制得(参见J.Heterocycl. Chem.16(1979)，333-337；也可参见EP-A 373464)。
还已知氯甲基吡啶类化合物也可通过在酸性接受体或自由基形成体存在下并在惰性稀释剂存在下，在0℃至100℃之间的温度下，氯化甲基吡啶类化合物而制得(参见EP-A 260485，也可参见EP-A458109)。
此外，已知烷氧基甲基吡啶类化合物通过与合适的氯化剂反应也可被转化成氯甲基吡啶类化合物(参见EP-A 393453)。
现已发现通式(I)的氯甲基吡啶类化合物，
其中：n代表数字0、1、2或3；和
X代表卤素；可通过将通式(II)的氨甲基吡啶类化合物
其中：n具有上面所给出的定义；和
X代表氨基或卤素；与亚硝基化剂或重氮化剂在稀释剂和任选在氯化氢存在下，在温度为-20℃到+50℃之间进行反应，然后按常规方法处理而以高产率制得。
令人吃惊的是，通式(I)的氯甲基吡啶类化合物按照本发明方法可以高产率制得。
本发明方法优选涉及制备式(I)化合物(其中n代表数字0、1或2，及X代表氟、氯或溴)。
具体地讲，本发明方法涉及制备3-氯甲基吡啶、2-氯-5-氯甲基吡啶和2，3-二氯-5-氯甲基吡啶。
例如，若用3-氨甲基吡啶和亚硝酰氯作起始物质，则本发明方法的反应路线可用下面的反应路线中的反应式来表示：
在本发明方法中用作起始物质的氨甲基吡啶类化合物一般由式(II)所定义。在式(II)中，n优选具有在将要按本发明方法制备的式(I)化合物的描述中所给出的n的优选意义，而X优选代表氨基、氟、氯或溴。
可提及的式(II)起始物质的实例有：3-氨甲基吡啶、2-氯-5-氨甲基吡啶、2-氨基-5-氨甲基吡啶和2，3-二氯-5-氨甲基吡啶。
式(II)起始物质是已知的和/或可按照本身已知的方法制备的(参见DEOS(德国公开说明书)3726993和WO 92/13840)。
用于制备式(I)的氯甲基吡啶类化合物的本发明方法是通过使用亚硝基化剂或重氮化剂进行的。适合的亚硝基化剂或重氮化剂特别是含有能容易地以亚硝酰基团(NO)断裂的组分的化合物。这些化合物优选包括亚硝酰氯、亚硝基硫酸和三氧化二氮以及亚硝酸烷基酯如亚硝酸甲酯、亚硝酸乙酯、亚硝酸丙酯和亚硝酸丁酯。亚硝酰氯特别优选用作本发明方法中的亚硝基化剂/重氮化剂。
本发明方法是在稀释剂存在下进行的。合适的稀释剂为常用的有机溶剂，例如(任选氯化)烃类如戊烷、己烷、庚烷、辛烷、环己烷、甲基环己烷、石油醚、汽油、轻石油、二氯甲烷、二氯乙烷、氯仿、四氯化碳、氯苯和邻二氯苯；醚类如乙醚、二丙醚、二异丙醚、二丁醚、二异丁醚、甲基叔丁基醚、甲基叔戊基醚、乙二醇二甲醚、四氢呋喃和二烷；酮类如丙酮、二乙基酮、甲基异丙基酮和甲基异丁基酮；酯类如乙酸甲酯和乙酸乙酯；腈类如乙腈和丙腈；酰胺类如N，N-二甲基甲酰胺、N，N-二乙基甲酰胺、N，N-二丙基甲酰胺、N，N-二丁基甲酰胺、N，N-二环己基甲酰胺和N，N-二甲基乙酰胺；其它如N-甲基吡咯烷酮、四甲基脲、二甲亚砜、四氢噻吩砜、液态二氧化硫和水。
水和上述有机溶剂(条件是它们实际上与水不混溶)的两相体系也可用作稀释剂，在此情况中优选使用相转移催化剂。可提及的这类催化剂的实例为：溴化四丁基铵、氯化四丁基铵、氯化四辛基铵、硫酸氢四丁基铵、氯化甲基三辛基铵、氯化十六烷基三甲基铵、溴化十六烷基三甲基铵、氯化苄基三甲基铵、氯化苄基三乙基铵、氢氧化苄基三甲基铵、氢氧化苄基三乙基铵、氯化苄基三丁基铵、溴化苄基三丁基铵、溴化四丁基鏻、氯化四丁基鏻、溴化三丁基十六烷基鏻，氯化丁基三苯基鏻、溴化乙基三辛基鏻、溴化四苯基鏻。
在本发明方法中反应温度可在较宽范围内变化。本方法一般在温度为-20℃至+50℃之间，优选为-10℃到+40℃之间进行。
本发明方法一般在大气压下或在略微加压或略微减压下，通常在1×104帕(0.1巴)到1×106帕(10巴)之间进行。
本发明方法一般在对于每1摩尔式(II)的氨甲基吡啶使用1到5摩尔，优选2到3摩尔的亚硝基化剂或重氮化剂的条件下进行。
在本发明方法优选的实施方案中，先将式(II)的氨甲基吡啶加入到一种上述稀释剂中，并在搅拌的同时加入规定量的亚硝基化剂或重氮化剂在一种上述稀释剂中的溶液。然后搅拌反应混合物直到反应结束；然后按常规方法处理所述混合物。
在本发明另一优选的实施方案中，先将亚硝基化剂或重氮化剂加入到一种上述稀释剂中，任选在氯化氢存在下，在搅拌的同时加入规定量的式(II)的氨甲基吡啶在一种上述稀释剂中的溶液。然后搅拌反应混合物直到反应结束；然后按常规方法处理所述混合物。
后处理可按常规方法进行。例如，反应混合物(任选在浓缩后)用水稀释，然后用氢氧化钠溶液或碳酸(氢)钠中和，有机相任选用与水实际上不混溶的有机溶剂(例如二氯甲烷)稀释。摇动后，把有机相分离出来，干燥并过滤。然后在减压下将有机溶剂从滤液中小心地蒸馏除去。所得到的式(I)的产品为油状残余物，它可用常规方法进一步纯化。
可按照本发明方法制备的式(I)的氯甲基吡啶类化合物可用作制备生物活性化合物如杀虫剂的中间体(参见EP-A 163855和EP-A192060)。
实例1
在10℃下在约90分钟内并在搅拌下将9.2克(141毫摩尔)亚硝酰氯的50毫升二氯甲烷溶液逐滴加入到10.0克(70毫摩尔)2-氯-5-氨甲基吡啶的200毫升二氯甲烷溶液中。然后在20℃将反应混合物进一步搅拌2小时。然后加入100毫升水并通过加入碳酸氢钠调节pH至7。把有机相分离出来，并且水相用二氯甲烷进一步萃取两次以上，每次用50ml。然后将溶剂在用水泵抽真空条件下从合并的有机相中小心蒸馏除去。
根据气相色谱法分析，所剩残余物含有6.8克(为理论量的60％)2-氯-5-氯甲基吡啶和3.5克(为理论量的35％)2-氯-5-羟甲基吡啶。
作为副产品得到的2-氯-5-羟甲基吡啶可以用常规方法分离出来并用已知方法(参见EP-A 373464)转变为2-氯-5-氯甲基吡啶。
实施例2
将25毫升N，N-二甲基甲酰胺在20℃时用氯化氢饱和。进一步用200毫升N，N-二甲基甲酰胺稀释此溶液，并在冷却至-10℃后，加入20毫升经预冷却的亚硝酰氯。使混合物的温度达到0℃。并在此温度下逐滴加入17.3克(122毫摩尔)2-氨基-5-氨甲基吡啶的100毫升N，N-二甲基甲酰胺溶液。然后使反应混合物的温度达到室温(20℃)，并在此温度下进一步搅拌1小时。然后在用水泵抽真空条件下将反应混合物浓缩，并通过加入50毫升0.2N氢氧化钠水溶液进行中和，并与150毫升二氯甲烷一起振摇。分离出有机相，用硫酸钠干燥后过滤。溶剂在用水泵抽真空的条件下从滤液中小心蒸馏除去。
根据1H-NMR谱分析，得到的14克油状物含有85％的2-氯-5-氯甲基吡啶(为理论量的60％)。
Claims (4)
1.制备通式(I)的氯甲基吡啶的方法
其中，X表示卤素，其特征在于通式(II)的氨基甲基吡啶
其中，X表示氨基或卤素与亚硝酰氯在有机稀释剂存在时在-20℃至+50℃温度下反应。
2.制备下面式子的2-氯-5-氯甲基吡啶的方法
其特征在于下面式子的2-氯-5-氨基甲基吡啶与亚硝酰氯在有机稀释剂存在时在-10℃至+40℃温度下反应。
3.根据权利要求2的方法，其特征在于反应在二氯甲烷中在+10℃至+20℃温度下进行。
4.根据权利要求2的方法，其特征在于反应在二甲基甲酰胺中在-10℃至+20℃温度下进行。
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| DEP4322054.1 | 1993-07-02 | ||
| DE4322054A DE4322054A1 (de) | 1993-07-02 | 1993-07-02 | Verfahren zur Herstellung von Chlormethylpyridinen |
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| CN102603620B (zh) * | 2012-01-13 | 2014-10-29 | 江苏中邦制药有限公司 | 一种氯甲基吡啶或其吡啶衍生物盐酸盐的合成方法 |
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| EP0508215A1 (de) * | 1991-04-06 | 1992-10-14 | Bayer Ag | Verfahren zur Herstellung von 2-Chlorpyridinen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105622494A (zh) * | 2015-10-15 | 2016-06-01 | 南京红太阳生物化学有限责任公司 | 一种2-氯-5-甲基吡啶的制备方法 |
| CN105622494B (zh) * | 2015-10-15 | 2019-01-15 | 南京红太阳生物化学有限责任公司 | 一种2-氯-5-甲基吡啶的制备方法 |
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| EP0632025A1 (de) | 1995-01-04 |
| JP3488930B2 (ja) | 2004-01-19 |
| JPH0717948A (ja) | 1995-01-20 |
| KR950003273A (ko) | 1995-02-16 |
| DE4322054A1 (de) | 1995-01-12 |
| CN1098405A (zh) | 1995-02-08 |
| KR100329100B1 (ko) | 2002-08-13 |
| TW253884B (zh) | 1995-08-11 |
| HUT67669A (en) | 1995-04-28 |
| ES2150960T3 (es) | 2000-12-16 |
| HU9401981D0 (en) | 1994-09-28 |
| US5442072A (en) | 1995-08-15 |
| DE59409558D1 (de) | 2000-11-30 |
| HU213626B (en) | 1997-08-28 |
| BR9402614A (pt) | 1995-04-04 |
| EP0632025B1 (de) | 2000-10-25 |
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