CN1101036A - 2-卤代-吡啶衍生物的制备方法 - Google Patents
2-卤代-吡啶衍生物的制备方法 Download PDFInfo
- Publication number
- CN1101036A CN1101036A CN 94103496 CN94103496A CN1101036A CN 1101036 A CN1101036 A CN 1101036A CN 94103496 CN94103496 CN 94103496 CN 94103496 A CN94103496 A CN 94103496A CN 1101036 A CN1101036 A CN 1101036A
- Authority
- CN
- China
- Prior art keywords
- methyl
- alkyl
- carbonyl
- pyridine
- chlorine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 125000001477 organic nitrogen group Chemical group 0.000 claims abstract description 16
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 230000002140 halogenating effect Effects 0.000 claims abstract description 7
- -1 nitro, formyl Chemical group 0.000 claims description 47
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000005660 chlorination reaction Methods 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 150000005749 2-halopyridines Chemical class 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 241000370738 Chlorion Species 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 3
- 125000004983 dialkoxyalkyl group Chemical group 0.000 claims description 3
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 3
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 3
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 claims description 2
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 150000001768 cations Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 abstract 2
- 150000001350 alkyl halides Chemical class 0.000 abstract 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 5
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 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
- 238000010257 thawing Methods 0.000 description 2
- XEMRAKSQROQPBR-UHFFFAOYSA-N (trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=CC=C1 XEMRAKSQROQPBR-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VXLYOURCUVQYLN-UHFFFAOYSA-N 2-chloro-5-methylpyridine Chemical compound CC1=CC=C(Cl)N=C1 VXLYOURCUVQYLN-UHFFFAOYSA-N 0.000 description 1
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 1
- AOSOZARHUJMBLZ-UHFFFAOYSA-N 2-fluoro-5-methylpyridine Chemical compound CC1=CC=C(F)N=C1 AOSOZARHUJMBLZ-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
- PEAOEIWYQVXZMB-UHFFFAOYSA-N 5-bromo-2-chloropyridine Chemical compound ClC1=CC=C(Br)C=N1 PEAOEIWYQVXZMB-UHFFFAOYSA-N 0.000 description 1
- ORIQLMBUPMABDV-UHFFFAOYSA-N 6-chloropyridine-3-carbonitrile Chemical compound ClC1=CC=C(C#N)C=N1 ORIQLMBUPMABDV-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BYMMIQCVDHHYGG-UHFFFAOYSA-N Cl.OP(O)(O)=O Chemical class Cl.OP(O)(O)=O BYMMIQCVDHHYGG-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 description 1
- IJJURYQDEVNZCW-UHFFFAOYSA-N bromophosphane Chemical compound BrP IJJURYQDEVNZCW-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical group Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003502 gasoline Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- BICAGYDGRXJYGD-UHFFFAOYSA-N hydrobromide;hydrochloride Chemical compound Cl.Br BICAGYDGRXJYGD-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000002897 organic nitrogen compounds Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 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 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 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
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 229940032912 zephiran Drugs 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
- C07D213/60—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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon 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
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及制备通式(I)的2-卤代-吡啶衍生
物的方法，式(I)中X和Y的意义如说明书中所
述，该方法的特征在于在第一步，如果适宜在稀释剂
存在下，将通式(II)的吡啶1-氧化物(其中Y如
说明书中所定义)与有机氮碱A和亲电子化合物反
应，得到通式(III)化合物(其中A，Y，Z-如说明
书中所定义)，如果适宜，分离出式(III)化合物作
为粗产物或者如果适宜可进一步纯化，在第二步，如
果适宜在烷基卤存在下以及如果适宜在稀释剂存在
下，于10℃和150℃之间的温度下将这些化合物与
卤化剂反应。另外，本发明还涉及新的式(III)化
合物。
Description
本发明涉及一种新的制备2-卤代-吡啶衍生物的方法以及用于此方法的新的中间产物。
已知，如果将相应的吡啶1-氧化物与磷酰氯（参照Chem.pharm.Bull.36（1988），2244-2247;和EP-A 324174/LeA 25745）、含氯磷酸衍生物（参照EP-A 370317/LeA 264 29）、酰氯（参照 EP-A 438691/LeA 27429）、磺酰氯（参照EP-A 463464/LeA 27658）或其它氯化剂（参照EP-A 439745/LeA 27472）反应可得到2-卤代-吡啶衍生物，如果适宜在碱性有机氮的化合物存在下进行。
但这些方法所达到的产率以及因此所得产物的质量在许多情况下并不令人满意，产物中经常含有大量异构体。
其中首先将3-甲基-吡啶1-氧化物与有机氮碱反应得到1∶1可被分离出的加合物，然后将后者与氯化剂反应制备2-氯代-5-甲基-吡啶的方法是以前尚未公开的在先专利申请的主题（参照DE-P 4204920/LeA 28939）。
现已发现用下述方法可以好的产率和优良的质量得到通式（Ⅰ）的2-卤代-吡啶衍生物：
其中
X 表示卤素，和
Y 表示卤素、硝基、甲酰基、氰基、羧基、氨基甲酰基、烷基、卤代烷基、烷氧基烷基、二烷氧基烷基、烷氧羰基、烷基氨基羰基或二烷基氨基羰基，
条件是除了其中X表示氯和Y同时表示甲基的化合物以外，此方法包括在第一步，如果适宜在稀释剂存在下，将下列通式（Ⅱ）的吡啶1-氧化物：
其中：
Y具有上述意义，
与有机氮碱A和亲电子化合物反应，得到下列通式（Ⅲ）化合物：
其中
A 表示有机氮碱基团
Y 具有上述意义，和
Z-表示由亲电子化合物形成的阴离子，
如果适宜，分离出式（Ⅲ）化合物作为粗产物或者如果适宜可进一步纯化，
在第二步中，如果适宜在烷基卤存在下以及如果适宜在稀释剂存在下，于10℃和150℃之间的温度下将这些化合物与卤化剂反应。
令人惊奇地是，利用本发明的方法可以以高产率和显著提高的异构体纯度得到式（Ⅰ）2-卤代-吡啶衍生物（与已知方法相比）。未反应的式（Ⅲ）中间产物还可以在此方法中再次使用。
因此，本发明方法极大地丰富了现有技术。
本发明方法优选涉及式（Ⅰ）化合物的制备方法，式（Ⅰ）中
X 表示氟、氯、溴或碘，和
Y 表示氟、氯、溴、碘、硝基、甲酰基、氰基、羧基或氨基甲酰基，或者表示任意地被氟、氯或溴取代的（一至三取代）或被C1-C4-烷氧基取代的（一或二取代）C1-C4-烷基，或表示C1-C4-烷氧羰基、C1-C4-烷基氨基-羰基或二-（C1-C4-烷基）氨基羰基。
本发明方法特别涉及式（Ⅰ）化合物的制备方法，式（Ⅰ）中
X 表示氟、氯或溴，和
Y 表示氟、氯、溴、甲酰基、氰基、羧基、氨基甲酰基、乙基、正-或异-丙基、正-，异-，仲-或叔-丁基、三氟甲基、三氯甲基、三溴甲基、二氟甲基、二氯甲基、二溴甲基、氟甲基、氯甲基、溴甲基、甲氧基甲基、乙氧甲基、正-或异-丙氧基甲基、正-，异-，仲-或叔-丁氧基甲基、二甲氧基甲基或二乙氧甲基、甲氧羰基、乙氧羰基、甲基氨基羰基、乙基氨基羰基、二甲基氨基羰基或二乙基氨基羰基。
例如，如果在第一步中用3-氟-吡啶1-氧化物作原料，三甲胺作有机氮碱A而光气作亲电子化合物和第二步中用光气作卤化剂，本发明方法的反应过程可通过下列反应式说明：
在本发明制备式（Ⅰ）化合物的方法中，式（Ⅱ）为用作反应原料的具有一般定义的吡啶1-氧化物。
式（Ⅱ）中Y优选或特别具有于本发明制备式（Ⅰ）化合物中所述上述已经定义的优选或特别优选的意义。
式（Ⅱ）反应原料是已知有机化学药品（参照J.Chem.Soc.1959，3680-3683，
J.Med.Chem.11（1968），1172-1176;Liebigs Ann.Chem.618（1958），152-158 and z. Chem 10（1970），184-185）。
式（Ⅲ）为在本发明方法第一步中所形成的具有一般定义的加合物。
式（Ⅲ）中优选
A 表示选自三-（C1-C4-烷基）胺、N，N-二-（C1-C4-烷基）苄胺、N，N-二-（C1-C4-烷基）环已胺的有机氮碱或表示任意地被C1-C4-烷基一至三取代的吡啶，和
Z-表示氯离子或C1-C4-烷基羧酸根离子;和
Y 优选具有本发明制备式（Ⅰ）化合物中所述上述已定义的优选意义。特别是式（Ⅲ）中
A 表示三甲胺、三乙胺、三丙胺、三丁胺、N，N-二甲基苄胺、N，N-二乙基苄胺，N，N-二甲基环已胺、N，N-二乙基环已胺，或者可任意地被甲基或乙基一或二取代的吡啶。
Z-表示氯离子或乙酸根离子，和
Y 特别具有本发明制备的式（Ⅰ）化合物中所
述上述已定义的特别优选的含义。
作为新的化合物，与在先申请DE-P 4204920相比，除了氯化三甲基-（5-甲基-吡啶-2-基）铵和氯化三乙基-（5-甲基-吡啶-2-基）铵之外，式（Ⅲ）加合物在文献中尚未公开，这也是本专利申请的一个主题。
在第一步中本发明方法可利用有机氮碱A进行。优选或特别优选的A的意义可见式（Ⅲ）化合物的定义。
本发明方法中作为有机氮碱，三甲胺是特别优选的。
本发明方法第一步中还使用了亲电子化合物，本发明方法优选的亲电子化合物是酰基氯或酸酐，例如乙酰氯、丙酰氯、乙酸酐、丙酸酐、苯甲酰氯、三氯甲苯、光气、草酰氯、苯磺酰氯、对甲苯磺酰氯、氯化磷（Ⅲ）、磷酰氯（三氯氧化磷）、氯化磷（Ⅴ）、亚硫酰氯、硫酰氯、氯化二氯亚甲基-二甲基亚铵、氰尿酰氯和三甲基氯硅烷。
光气、亚硫酰氯、硫酰氯、苯磺酰氯和对甲苯磺酰氯是用于本发明方法的特别优选的亲电子物质。
第二步中本发明方法可利用卤化剂进行。本发明方法中优选的卤化剂是能够向其它反应物提供卤素离子的化合物，例如乙酰氯、苯甲酰氯、光气、草酰氯、苯磺酰氯、氯化磷（Ⅲ）、溴化磷（Ⅲ）、磷酰氯、氯化磷（Ⅴ）、亚硫酰氯、硫酰氯、氯化氢、氟化氢、溴化氢、氯化四乙基铵、氯化四丁基铵和氯化苄基-三乙基铵。
光气、氟化氢、氯化氢和溴化氢是本发明方法第二步中特别优选的卤化剂。
在第二步中如果适宜，本发明方法可在烷基卤存在下进行。优选的烷基氯有氯代甲烷、溴代甲烷、氯代乙烷、氯代丙烷和氯代丁烷、特别优选氯代甲烷。
在第一步中本发明方法优选利用稀释剂进行。可能的稀释剂包括实际上所有惰性有机溶剂，优选包括脂肪族和芳香族的、任意卤代的烃，例如戊烷、已烷、庚烷、环已烷、石油醚、汽油、轻汽油、苯、甲苯、二甲苯、二氯甲烷、二氯乙烷、氯仿、四氯化碳、氯苯和邻二氯苯、醚例如乙醚和丁醚、乙二醇二甲醚和二乙二醇二甲醚、四氢呋喃和二噁烷、酮例如丙酮和甲基乙基酮、甲基异丙基酮和甲基异丁基酮、酯例如乙酸甲酯和乙酯、腈例如乙腈和丙腈、酰胺例如二甲基甲酰胺、二甲基乙酰胺和N-甲基吡咯烷酮以及二甲亚砜，四氢噻吩砜和六甲基磷酸三酰胺。
如果适宜，在第二步中本发明方法也可以在稀释剂存在下进行。在此可能的稀释剂，除水以外，包括实际上所有惰性有机溶剂，优选包括醇例如甲醇、乙醇以及正-和异-丙醇、羧酸例如甲酸、乙酸和丙酸以及上述本发明方法第一步中所提及的溶剂。
如果使用三甲胺作为有机氮碱，由本发明方法第一步通常在-50℃和+120℃之间，优选-30℃和+80℃之间的温度范围内进行。如果使用非三甲胺的有机氮碱，则第一步通常在-30℃至+100℃，优选-15℃和+10℃之间的温度范围内进行。
本发明方法第一步通常在常压下进行。然而在升压或减压下，通常在0.1和100巴之间，也可进行第一步反应。
为了进行本发明方法第一步反应，每摩尔式（Ⅱ）起始化合物通常使用1-10摩尔，优选1-5摩尔有机氮碱和1-10摩尔，优选1-5摩尔亲电子化合物。
在本发明方法第一步的优选实施方案中，最初向稀释剂中加入式（Ⅱ）起始化合物，冷却后，于搅拌下依次缓慢地计量加入有机氮碱然后是亲电子化合物。
如果适宜，在反应完成后，可于减压下蒸除较易挥发的组分。基本上含有式（Ⅲ）加合物的粗中间产物可用常规方法例如经柱色谱法纯化，或者也可以以粗产物形式用于第二步反应中。
优选的是将如此所得的粗中间产物-如果适宜也未除去稀释剂-直接用于第二步反应中。
本发明方法第二步通常是在10℃和150℃之间，优选20℃和120℃之间，特别是30℃和110℃之间的温度范围内进行。
本发明方法第二步通常是在常压下进行的。但在加压或减压下通常在0.01-200巴之间也可进行第二步反应。
后处理可用常规方法进行。例如粗产物可用与水几乎不混溶的有机溶剂浸提，用水洗涤并干燥。于减压下通过蒸馏小心地除掉有机溶剂后，得到基本上含有式（Ⅰ）产物的残余物。
利用本发明方法制备的2-卤代-吡啶衍生物可以在药物（参照DE-A 2812585）或植物治疗剂（参照DE-A2630046，EP-A 192060，DE-A3726993和DE-A 3924682）的制备中用作中间产物。
制备实施例：
实施例1
第一步：
于-25℃下将47.2g（0.8mol）三甲胺加入到32.4g（0.25mol）3-氯代吡啶N-氧化物的250ml1，2-二氯乙烷溶液中，在40分钟内于0℃滴加入52.95g（0.31mol）苯磺酰氯。将混合物于0℃搅拌2小时，然后令其融化过夜。于低于50℃的浴温下将其真空浓缩，残余物经反复柱色谱法纯化。
得到24.3g（理论产率的47%）氯化三甲基-2-（5-氯代吡啶基）铵。1H-NMR（300 MHz，D6-DMSO：δ/ppm＝3.63（9H，s），8.25（IH，d，J＝8.7Hz），8.42（IH，dd，J1＝9 Hz，J2＝2.4Hz，8.77（IH，d，J＝2.4Hz）。
第二步：
按照上述方法由32.4g（0.25mol）3-氯代吡啶N-氧化物制得氯化三甲基-2-（5-氯代吡啶基）铵，但粗产物未经柱色谱法纯化。将粗产物加入到500ml 1，2-二氯乙烷中并于50℃下通入氯化氢气达30小时。然后将混合物浓缩，残余物溶于水中，该混合物用稀氢氧化钠溶液调至pH9-10并用二氯甲烷萃取3次。合并的有机相用硫酸钠干燥，过滤并于旋转蒸发仪上浓缩，粗产物经色谱法纯化。
得到19.7g（理论产率的53%，以所用的3-氯代吡啶N-氧化物计）2，5-二氯吡啶。
实施例2
第一步：
于-25℃下将41.9g（0.71mol）三甲胺加入到37.4g（0.215mol）3-溴代吡啶N-氧化物的250ml1，2-二氯乙烷溶液中。在1小时内于0℃滴加入45.6g（0.258mol）苯磺酰氯。随后将混合物于0℃搅拌2小时并令其融化过夜。将其于低于50℃的浴温下真空浓缩，残余物经数次柱色谱层析纯化。
得到27.4g（理论产率的50.7%）氯化三甲基-2-（5-溴代吡啶基）铵。
1H-NMR（300 MHz，D6-DMSO：δ/ppm＝3.61（9H，s），8.145（IH，d，J＝8.7Hz），8.54（IH，dd，J1＝9 Hz，J2＝2.4Hz，8.85（IH，d，J＝2.4Hz）。
第二步：
按照上述方法由52.2g（0.3mol）3-溴代吡啶N-氧化物制得氯化三甲基-2-（5-溴代吡啶基）铵，但粗产物未经柱色谱法纯化。将粗产物加入到500ml 1，2-二氯乙烷中并于50℃下通入氯化氢气30小时。然后将混合物浓缩，残余物溶于水中，该混合物用稀氢氧化钠溶液碱化（pH9-10）并用二氯甲烷萃取3次。合并的有机相用硫酸钠干燥，过滤并于旋转蒸发仪上浓缩，粗产物经色谱法纯化。
得到32.7g（理论产率的56.6%，以所用3-溴代吡啶N-氧化物计）5-溴代-2-氯代吡啶。
实施例3
将6g（0.03mol）氯化三甲基-2-（5-氰基吡啶基）铵加入到80ml 1，2-二氯乙烷中并于50℃通入氯化氢气5小时。然后将混合物浓缩，残余物溶于水中，该混合物用氢氧化钠溶液调至pH9-10并用二氯甲烷萃取3次。合并的有机相用硫酸钠干燥，过滤并于旋转蒸发仪上浓缩。
得到3.8g（理论产率的91%）2-氯代-5-氰基吡啶。
实施例4
先将54.5g（0.5mol）3-甲基吡啶1-氧化物加入到350ml二氯甲烷中并将混合物冷却至0℃，于此温度下向该混合物中加入202g（2mol）三甲胺，然后通入148.5g（1.6mol）光气，期间通过充分冷却使温度保持在0℃。当反应完成时于20℃用水泵抽真空除去过量的光气。将所剩残余物溶于350ml 1，2-二氯乙烷中并加入30g（1.5mol）无水氟化氢。将装置密封并施加10巴氮气压并将混合物加热至120℃，将其于此温度下搅拌20小时。然后使其冷却，用水泵抽真空除去过量的氟化氢并将残余物倾入冰中。混合物用固体氢氧化钾使之呈碱性，然后用二氯甲烷萃取。有机相经干燥并浓缩后，将残余物蒸馏。
得到38g（理论产率的68.5%）2-氟代-5-甲基吡啶（b.p.48-45＝65-75℃）。
Claims (6)
1、制备通式(Ⅰ)的2-卤代-吡啶衍生物的方法，
其中
X表示卤素，和
Y表示卤素、硝基、甲酰基、氰基、羧基、氨基甲酰基、烷基、卤代烷基、烷氧基烷基、二烷氧基烷基、烷氧羰基、烷基氨基羰基或二烷基氨基羰基，
条件是除了其中X表示氯和Y同时表示甲基的化合物以外，其特征在于第一步，如果适宜在稀释剂存在下，将下列通式(Ⅱ)的吡啶1-氧化物：
其中：
Y具有上述意义，
与有机氮碱A和亲电子化合物反应，得到下列通式(Ⅲ)化合物：
其中
A表示有机氮碱基团
Y具有上述意义，和
Z-表示由亲电子化合物形成的阴离子，
如果适宜，分离出式(Ⅲ)化合物作为粗产物或者如果适宜可进一步纯化，
在第二步中，如果适宜在烷基卤存在下以及如果适宜在稀释剂存在下，于10℃和150℃之间的温度下将这些化合物与卤化剂反应。
2、根据权利要求1的方法，其特征在于：
X 表示氟、氯、溴或碘，和
Y 表示氟、氯、溴、碘、硝基、甲酰基、氰基、羧基或氨基甲酰基，或者表示任意地被氟、氯或溴取代的（一至三取代）或被C1-C4-烷氧基取代的（一或二取代）C1-C4-烷基，或表示C1-C4-烷氧羧基、C1-C4-烷基氨基-羰基或二-（C1-C4-烷基）氨基羰基，
条件是除了其中X表示氯和Y同时表示甲基的化合物以外。
3、根据权利要求1的方法，其特征在于：
X 表示氟、氯或溴，和
Y 表示氟、氯、溴、甲酰基、氰基、羧基、氨基甲酰基、乙基、正-或异-丙基、正-，异-，仲-或叔-丁基、三氟甲基、三氯甲基、三溴甲基、二氟甲基、二氯甲基、二溴甲基、氟甲基、氯甲基、溴甲基、甲氧基甲基、乙氧甲基、正-或异-丙氧基甲基、正-，异-，仲-或叔-丁氧基甲基、二甲氧基甲基或二乙氧甲基、甲氧羰基、乙氧羰基、甲基氨基羰基、乙基氨基羰基、二甲基氨基羰基或二乙基氨基羰基。
4、下列式（Ⅲ）化合物：
其中
A 表示有机氮碱的阳离子基团，
Z 表示亲电子化合物上形成的阴离子，和
Y 表示卤素、硝基、甲酰基、氰基、羧基、氨基甲酰基、烷基、卤代烷基、烷氧基烷基、二烷氧基烷基、烷氧羰基、烷基氨基羰基或二烷基氨基羰基，
条件是除了氯化三甲基-（5-甲基-吡啶-2-基）铵和氯化三乙基-（5-甲基-吡啶-2-基）铵以外。
5、根据权利要求4的式（Ⅲ）化合物，其中
A 表示选自包含三-（C1-C4-烷基）胺、N，N-二-（C1-C4-烷基）苄胺、N，N-二-（C1-C4-烷基）环已胺的有机氮碱或表示任意地被C1-C4-烷基一至三取代的吡啶，和
Z-表示氯离子或C1-C4-烷基羧酸根离子;和
Y 表示氟、氯、溴、碘、硝基、甲酰基、氰基、羧基或氨基甲酰基，或者表示任意地被氟、氯或溴取代的（一至三取代）或被C1-C4-烷氧基取代的（一或二取代）C1-C4-烷基，或表示C1-C4-烷氧羰基、C1-C4烷基氨基羰基或二-（C1-C4-烷基）氨基羰基，
条件是除了氯化三甲基-（5-甲基-吡啶-2-基）铵和氯化三乙基-（5-甲基-吡啶-2-基）铵以外。
6、根据权利要求4的式（Ⅲ）化合物，其中
A 表示三甲胺、三乙胺、三丙胺、三丁胺、N，N-二甲基苄胺、N，N-二乙基苄胺，N，N-二甲基环已胺、N，N-二乙基环已胺，或者任意地被甲基或乙基一或二取代的吡啶。
Z-表示氯离子或乙酸根离子，和
Y 表示氟、氯、溴、甲酰基、氰基、羧基、氨基甲酰基、乙基、正-或异-丙基、正-，异-，仲-或叔-丁基、三氟甲基、三氯甲基、三溴甲基、二氟甲基、二氯甲基、二溴甲基、氟甲基、氯甲基、溴甲基、甲氧基甲基、乙氧基甲基、正-或异-丙氧基甲基、正-，异-，仲或叔-丁氧基甲基、二甲氧基甲基或二乙氧基甲基、甲氧羰基、乙氧羰基、甲基氨基羰基、乙基氨基羰基、二甲基氨基羰基或二乙基氨基羰基，
条件是除了氯化三甲基-（5-甲基-吡啶-2-基）铵和氯化三乙基-（5-甲基-吡啶-2-基）铵以外。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19934311247 DE4311247A1 (de) | 1993-04-06 | 1993-04-06 | Verfahren zur Herstellung von 2-Halogen-pyridin-derivaten |
| DEP4311247.1 | 1993-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1101036A true CN1101036A (zh) | 1995-04-05 |
Family
ID=6484851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 94103496 Pending CN1101036A (zh) | 1993-04-06 | 1994-04-06 | 2-卤代-吡啶衍生物的制备方法 |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0619307A1 (zh) |
| JP (1) | JPH06306049A (zh) |
| CN (1) | CN1101036A (zh) |
| BR (1) | BR9401396A (zh) |
| DE (1) | DE4311247A1 (zh) |
| HU (1) | HUT67563A (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105579454A (zh) * | 2013-09-26 | 2016-05-11 | 伊莱利利公司 | 化合物及其用于制备Tau成像剂和Tau成像制剂的用途 |
| CN113235116A (zh) * | 2021-05-12 | 2021-08-10 | 齐鲁工业大学 | 一种溴代吡啶衍生物的电化学合成方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4020055A1 (de) * | 1990-01-18 | 1991-07-25 | Bayer Ag | Verfahren zur herstellung von substituierten 2-chlor-pyridinen |
| DE4020053A1 (de) * | 1990-01-31 | 1991-08-01 | Bayer Ag | Verfahren zur herstellung von 2-chlor-5-methyl-pyridin |
| DE4020052A1 (de) * | 1990-06-23 | 1992-01-02 | Bayer Ag | Verfahren zur herstellung von 2-chlor-5-methyl-pyridin |
| DE4212595A1 (de) * | 1992-02-19 | 1993-08-26 | Bayer Ag | Verfahren zur herstellung von 2-chlor-5-methyl-pyridin |
-
1993
- 1993-04-06 DE DE19934311247 patent/DE4311247A1/de not_active Withdrawn
-
1994
- 1994-03-24 EP EP94104674A patent/EP0619307A1/de not_active Withdrawn
- 1994-03-31 JP JP8373794A patent/JPH06306049A/ja active Pending
- 1994-04-05 BR BR9401396A patent/BR9401396A/pt not_active Application Discontinuation
- 1994-04-06 HU HU9400973A patent/HUT67563A/hu unknown
- 1994-04-06 CN CN 94103496 patent/CN1101036A/zh active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105579454A (zh) * | 2013-09-26 | 2016-05-11 | 伊莱利利公司 | 化合物及其用于制备Tau成像剂和Tau成像制剂的用途 |
| CN113235116A (zh) * | 2021-05-12 | 2021-08-10 | 齐鲁工业大学 | 一种溴代吡啶衍生物的电化学合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0619307A1 (de) | 1994-10-12 |
| DE4311247A1 (de) | 1994-10-13 |
| HU9400973D0 (en) | 1994-06-28 |
| JPH06306049A (ja) | 1994-11-01 |
| BR9401396A (pt) | 1994-10-18 |
| HUT67563A (en) | 1995-04-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Colantoni et al. | Aza-Michael addition of nosyloxycarbamates to 2-(trifluoromethyl) acrylates | |
| KR19980018089A (ko) | 트랜스아제티디논의 입체선택적 제조방법 | |
| CN1718572A (zh) | 制备环－氟化的芳香族化合物的改进方法 | |
| CN1839120A (zh) | 顺－4－氟－l－脯氨酸衍生物的制备方法 | |
| CN1127114A (zh) | 取代的4-苯基-6-氨基烟酸衍生物作为药物的应用 | |
| CN1161329A (zh) | 1，3-二甲基-5-氟吡唑-4-(n-苯基)甲酰胺类化合物的制法 | |
| CN1040431C (zh) | 2-氯-5-甲基吡啶的制备方法 | |
| CN1882592A (zh) | 维生素b6的制备 | |
| JP2007230963A (ja) | ２，４−ジ置換ピリジンの製造法 | |
| CN1101036A (zh) | 2-卤代-吡啶衍生物的制备方法 | |
| CN1106009A (zh) | 咪唑并吡啶类衍生物的制备方法 | |
| CN1022920C (zh) | 五元含氮杂环芳香物质的制备方法 | |
| CN111362795B (zh) | 一类取代丁酸酯类衍生物的制备方法 | |
| CN1297539C (zh) | 氨基吡咯烷衍生物的制备方法 | |
| CN1846696A (zh) | 对映体纯的n－甲基－n－[(1s)－1－苯基－2－((3s)－3－羟基吡咯烷－1－基)乙基]－2,2－二苯基乙酰胺的制备方法 | |
| CN101056857A (zh) | 异烟酸衍生物的制备方法 | |
| CN109851599B (zh) | 一种2-氨基苯并呋喃化合物的制备方法 | |
| CN1132817C (zh) | 制备杂芳基甲酰胺和酯的方法 | |
| CN101691319B (zh) | 一种合成氟代含氮杂环化合物的方法 | |
| CN1158249C (zh) | 制备杀虫剂中间体的方法 | |
| CN1019969C (zh) | 共轭羧基链烯酸的合成方法 | |
| JP4524845B2 (ja) | アミノ基を有する光学活性アリルアルコール誘導体の製造方法、および光学活性化合物 | |
| JPS60158137A (ja) | 含フツ素アクリル酸誘導体の製法 | |
| Ghaffarzadeh et al. | High yield synthesis of aryl cyanides under microwave irradiation | |
| CN116284126A (zh) | 一种二芳基膦酰基-4-氟-3-丁烯-1-酮化合物及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |