CN102947270B - 制备4-羟基吡啶的方法 - Google Patents
制备4-羟基吡啶的方法 Download PDFInfo
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- CN102947270B CN102947270B CN201180031044.5A CN201180031044A CN102947270B CN 102947270 B CN102947270 B CN 102947270B CN 201180031044 A CN201180031044 A CN 201180031044A CN 102947270 B CN102947270 B CN 102947270B
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- Prior art keywords
- alkyl
- haloalkyl
- alkali
- hydrogen
- acid
- Prior art date
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- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical class OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 239000011541 reaction mixture Substances 0.000 claims description 28
- -1 alkali metal ethoxide Chemical class 0.000 claims description 27
- 239000003513 alkali Substances 0.000 claims description 23
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 21
- 229910021529 ammonia Inorganic materials 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 238000010306 acid treatment Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000007848 Bronsted acid Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 3
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 0 *c1c(*)nc(*)c(*)c1Cl Chemical compound *c1c(*)nc(*)c(*)c1Cl 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-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
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- IJOSVNBGIKAARU-UHFFFAOYSA-N 3-chloro-2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=NC=CC=C1Cl IJOSVNBGIKAARU-UHFFFAOYSA-N 0.000 description 1
- PJCCSZUMZMCWSX-UHFFFAOYSA-N 4,4-Dimethoxy-2-butanone Chemical compound COC(OC)CC(C)=O PJCCSZUMZMCWSX-UHFFFAOYSA-N 0.000 description 1
- VNZOLPIHDIJPBZ-UHFFFAOYSA-N 4-hydroxypyran-2-one Chemical compound OC=1C=COC(=O)C=1 VNZOLPIHDIJPBZ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000004936 P-84 Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- ZKBNUNIVNISNDB-UHFFFAOYSA-N [Cl].FC Chemical compound [Cl].FC ZKBNUNIVNISNDB-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VTJUKNSKBAOEHE-UHFFFAOYSA-N calixarene Chemical compound COC(=O)COC1=C(CC=2C(=C(CC=3C(=C(C4)C=C(C=3)C(C)(C)C)OCC(=O)OC)C=C(C=2)C(C)(C)C)OCC(=O)OC)C=C(C(C)(C)C)C=C1CC1=C(OCC(=O)OC)C4=CC(C(C)(C)C)=C1 VTJUKNSKBAOEHE-UHFFFAOYSA-N 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
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- 239000002739 cryptand Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HABLENUWIZGESP-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O HABLENUWIZGESP-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- JVHJRIQPDBCRRE-UHFFFAOYSA-N ethyl 2,2,3,3,4,4,4-heptafluorobutanoate Chemical compound CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F JVHJRIQPDBCRRE-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- KYYWBEYKBLQSFW-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O KYYWBEYKBLQSFW-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-O hexylazanium Chemical compound CCCCCC[NH3+] BMVXCPBXGZKUPN-UHFFFAOYSA-O 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- NDNOUXQCMAHOSA-UHFFFAOYSA-N methyl 2,2,3,3-tetrafluoro-3-methoxypropanoate Chemical class COC(=O)C(F)(F)C(F)(F)OC NDNOUXQCMAHOSA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- NZMAJUHVSZBJHL-UHFFFAOYSA-N n,n-dibutylformamide Chemical compound CCCCN(C=O)CCCC NZMAJUHVSZBJHL-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peroxyacetic acid Substances CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000004476 plant protection product Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 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
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- PDSVZUAJOIQXRK-UHFFFAOYSA-N trimethyl(octadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)C PDSVZUAJOIQXRK-UHFFFAOYSA-N 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene 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
- C07D213/60—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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种制备式I的4-羟基吡啶的方法,其中R1、R2、R3和R4具有如说明书中所定义的含义。
Description
本发明涉及一种制备4-羟基吡啶的方法。
由于取代吡啶优异的多功能性以及它们作为活性物质组分,尤其是医用药物和植物保护剂组分的用途,取代吡啶的合成已经成为深入研究的主题。
Tyvorskii等人已公开了在强碱叔丁醇钾的存在下使乙酰丙酮烯醇醚与全氟链烷酸乙酯反应,随后酸催化环化而得到取代的吡喃酮(Tetrahedron 54(1998),2819-2826)。Tyvorskii等人已公开了通过类似合成方法制备2-三氟甲基-4H-吡喃-4-酮(Chem.Heterocycl.Comp.33(1997),995)。分离该吡喃酮,并将氨水加入吡喃酮溶液中,得到4-羟基-2-三氟甲基吡啶。吡啶的总收率仅为40%×70%=28%。
WO 2008/074474描述了一种制备O-改性4-羟基吡啶衍生物的多步方法,该方法包括使1,3-二酮与氨反应,随后将所得α,β-不饱和的β-氨基酮与羧酸卤化物或酸酐进行N-酰基化,然后通过分子内羟醛缩合成环,以3个步骤约50-60%的收率得到取代的4-羟基吡啶。
本发明寻找能够以易得原料起始并能以高收率非常经济地进行的制备取代的4-羟基吡啶的合成方法。
本发明涉及一种制备式I的4-羟基吡啶的方法:
其中
R1为氢、C1-C4烷基、C1-C4卤代烷基、芳基或杂芳基,其中后提到的两个基团未被取代或者被选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;
R2、R3和R4独立地为氢、C1-C4烷基、C1-C4卤代烷基、NR5R6或芳基,其中芳基未被取代或者被1、2、3或4个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;
或者基团R3和R4与它们所键合的碳原子一起形成3、4、5、6或7元饱和、部分不饱和或最大程度不饱和的碳环或者包含1、2或3个选自O、S和N的杂原子作为环成员的3、4、5、6或7元饱和、部分不饱和或最大程度不饱和的杂环,其中碳环或杂环未被取代或者被1、2、3或4个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;
R5为氢、C1-C4烷基或C1-C4卤代烷基;
R6为氢、C1-C4烷基、C1-C4卤代烷基、苯基和苯基-C1-C4烷基;或者R5和R6一起形成线性C4-或C5-亚烷基桥或基团-CH2CH2OCH2CH2-或-CH2CH2NR7CH2CH2-;并且
R7为氢或C1-C4烷基;
所述方法包括:
a)将式II化合物:
其中R1如上所定义;
X为卤素或C1-C4烷氧基;
与式IIIa或IIIb化合物:
其中R2、R3、R4如上所定义;
Y独立地为卤素或C1-C4烷氧基;
或者式IIIa化合物中的两个基团Y一起形成基团-O-(CH2)n-O-,其中链烷二基结构部分-(CH2)n-未被取代或者被1、2或3个选自卤素和C1-C4烷基的取代基取代;并且
n为2、3或4;
以及至少一种选自碱金属甲醇盐或碱金属乙醇盐的碱混合,形成反应混合物;
b)在第一反应期后,将所述反应混合物用至少一种酸处理;以及
c)在第二反应期后,将所述反应混合物用至少一种氨源处理。
除非另有定义,本文所用的通用术语具有下列含义:
术语“卤素”表示氟、氯、溴或碘,尤其是氟、氯或溴。
术语“C1-C4烷基”表示包含1-4个碳原子的线性或支化烷基,例如甲基、乙基、丙基、1-甲基乙基(异丙基)、丁基、1-甲基丙基(仲丁基)、2-甲基丙基(异丁基)或1,1-二甲基乙基(叔丁基)。
术语“C1-C4卤代烷基”表示具有1-4个碳原子的直链或支化烷基,其中这些基团中的一些或全部氢原子已被卤原子替换。其实例为氯甲基、溴甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基、氯氟甲基、二氯一氟甲基、一氯二氟甲基、1-氯乙基、1-溴乙基、1-氟乙基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、2-氯-2-氟乙基、2-氯-2,2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基、五氟乙基、3,3,3-三氟丙-1-基、1,1,1-三氟丙-2-基、3,3,3-三氯丙-1-基、七氟异丙基、1-氯丁基、2-氯丁基、3-氯丁基、4-氯丁基、1-氟丁基、2-氟丁基、3-氟丁基、4-氟丁基等。
同样地,术语“C1-C4全卤代烷基”表示具有1-4个碳原子的直链或支化烷基,其中这些基团中的全部氢原子已被卤原子替换。其实例为三氟甲基、三氯甲基、五氟乙基、七氟丙基等。
术语“C1-C4烷氧基”表示经由氧原子连接的包含1-4个碳原子的直链或支化饱和烷基。C1-C4烷氧基的实例为甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(异丙氧基)、正丁氧基、1-甲基丙氧基(仲丁氧基)、2-甲基丙氧基(异丁氧基)和1,1-二甲基乙氧基(叔丁氧基)。
术语“芳基”表示具有6-14个碳原子的碳环芳族基团。其实例包括苯基、萘基、芴基、薁基、蒽基和菲基。芳基优选为苯基或萘基,尤其是苯基。
术语“杂芳基”表示具有1-4个选自O、N和S的杂原子的芳族基团。其实例为具有1、2、3或4个选自O、S和N的杂原子的5和6元杂芳基,例如吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、唑基、异唑基、噻唑基、异噻唑基、三唑基、四唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基和三嗪基。
术语“化合物I”、“化合物II”、“化合物IIIa”和“化合物IIIb”分别是指式I、II、IIIa和IIIb的化合物。
在化合物I和II中,R1优选为氢、C1-C4烷基或C1-C4卤代烷基。R1更优选为C1-C4全卤代烷基,更优选C1-C2全卤代烷基,例如三氟甲基或五氟乙基,尤其是三氟甲基。
在化合物I、IIIa和IIIb中,R2、R3、R4优选为氢、C1-C4烷基或C1-C4卤代烷基,尤其是氢。
在化合物II中,X优选为C1-C4烷氧基,更优选甲氧基或乙氧基。
在化合物IIIa和IIIb中,Y优选为氯或C1-C4烷氧基,更优选C1-C4烷氧基,尤其是甲氧基或乙氧基。
在化合物IIIa和IIIb中,R3和R4优选也可不与它们连接的碳原子一起形成碳环或杂环;更优选可相互独立地为氢、C1-C4烷基、C1-C4卤代烷基、NR5R6或芳基,其中芳基未被取代或被1、2、3或4个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;其中R5和R6如上所定义;或者甚至更优选R3和R4可为氢或C1-C4烷基。
特别优选的实施方案涉及化合物I的制备,其中化合物I带有如下表P中所定义的R1、R2、R3和R4的下列组合之一。如果适用的话,这些实施方案也指化合物II、IIIa和IIIb中相同取代基的定义。
表P:
行F | R1 | R2 | R3 | R4 |
P-1 | H | H | H | H |
P-2 | CH3 | H | H | H |
P-3 | C2H5 | H | H | H |
P-4 | C3H7 | H | H | H |
P-5 | CClF2 | H | H | H |
P-6 | CCl2F | H | H | H |
P-7 | CF3 | H | H | H |
P-8 | CHF2 | H | H | H |
P-9 | CH2F | H | H | H |
P-10 | CF2CH3 | H | H | H |
行F | R1 | R2 | R3 | R4 |
P-11 | CCl2CH3 | H | H | H |
P-12 | CF2CF3 | H | H | H |
P-13 | CCl2CCl3 | H | H | H |
P-14 | CF2CHF2 | H | H | H |
P-15 | CF2CF2CF3 | H | H | H |
P-16 | CCl2CCl2CCl3 | H | H | H |
P-17 | CF2CF2OCH3 | H | H | H |
P-18 | H | CH3 | H | H |
P-19 | CH3 | CH3 | H | H |
P-20 | C2H5 | CH3 | H | H |
P-21 | C3H7 | CH3 | H | H |
P-22 | CClF2 | CH3 | H | H |
P-23 | CCl2F | CH3 | H | H |
P-24 | CF3 | CH3 | H | H |
P-25 | CHF2 | CH3 | H | H |
P-26 | CH2F | CH3 | H | H |
P-27 | CF2CH3 | CH3 | H | H |
P-28 | CCl2CH3 | CH3 | H | H |
P-29 | CF2CF3 | CH3 | H | H |
P-30 | CCl2CCl3 | CH3 | H | H |
P-31 | CF2CHF2 | CH3 | H | H |
P-32 | CF2CF2CF3 | CH3 | H | H |
P-33 | CCl2CCl2CCl3 | CH3 | H | H |
P-34 | CF2CF2OCH3 | CH3 | H | H |
P-35 | H | H | CH3 | H |
P-36 | CH3 | H | CH3 | H |
P-37 | C2H5 | H | CH3 | H |
P-38 | C3H7 | H | CH3 | H |
P-39 | CClF2 | H | CH3 | H |
P-40 | CCl2F | H | CH3 | H |
P-41 | CF3 | H | CH3 | H |
P-42 | CHF2 | H | CH3 | H |
P-43 | CH2F | H | CH3 | H |
P-44 | CF2CH3 | H | CH3 | H |
P-45 | CCl2CH3 | H | CH3 | H |
P-46 | CF2CF3 | H | CH3 | H |
P-47 | CCl2CCl3 | H | CH3 | H |
P-48 | CF2CHF2 | H | CH3 | H |
行F | R1 | R2 | R3 | R4 |
P-49 | CF2CF2CF3 | H | CH3 | H |
P-50 | CCl2CCl2CCl3 | H | CH3 | H |
P-51 | CF2CF2OCH3 | H | CH3 | H |
P-52 | H | H | H | CH3 |
P-53 | CH3 | H | H | CH3 |
P-54 | C2H5 | H | H | CH3 |
P-55 | C3H7 | H | H | CH3 |
P-56 | CClF2 | H | H | CH3 |
P-57 | CCl2F | H | H | CH3 |
P-58 | CF3 | H | H | CH3 |
P-59 | CHF2 | H | H | CH3 |
P-60 | CH2F | H | H | CH3 |
P-61 | CF2CH3 | H | H | CH3 |
P-62 | CCl2CH3 | H | H | CH3 |
P-63 | CF2CF3 | H | H | CH3 |
P-64 | CCl2CCl3 | H | H | CH3 |
P-65 | CF2CHF2 | H | H | CH3 |
P-66 | CF2CF2CF3 | H | H | CH3 |
P-67 | CCl2CCl2CCl3 | H | H | CH3 |
P-68 | CF2CF2OCH3 | H | H | CH3 |
P-69 | H | H | H | CH3 |
P-70 | CH3 | H | H | CH3 |
P-71 | C2H5 | H | H | CH3 |
P-72 | C3H7 | H | H | CH3 |
P-73 | CClF2 | H | H | CH3 |
P-74 | CCl2F | H | H | CH3 |
P-75 | CF3 | H | H | CH3 |
P-76 | CHF2 | H | H | CH3 |
P-77 | CH2F | H | H | CH3 |
P-78 | CF2CH3 | H | H | CH3 |
P-79 | CCl2CH3 | H | H | CH3 |
P-80 | CF2CF3 | H | H | CH3 |
P-81 | CCl2CCl3 | H | H | CH3 |
P-82 | CF2CHF2 | H | H | CH3 |
P-83 | CF2CF2CF3 | H | H | CH3 |
P-84 | CCl2CCl2CCl3 | H | H | CH3 |
P-85 | CF2CF2OCH3 | H | H | CH3 |
P-86 | H | CF3 | H | H |
行F | R1 | R2 | R3 | R4 |
P-87 | CH3 | CF3 | H | H |
P-88 | C2H5 | CF3 | H | H |
P-89 | C3H7 | CF3 | H | H |
P-90 | CClF2 | CF3 | H | H |
P-91 | CCl2F | CF3 | H | H |
P-92 | CF3 | CF3 | H | H |
P-93 | CHF2 | CF3 | H | H |
P-94 | CH2F | CF3 | H | H |
P-95 | CF2CH3 | CF3 | H | H |
P-96 | CCl2CH3 | CF3 | H | H |
P-97 | CF2CF3 | CF3 | H | H |
P-98 | CCl2CCl3 | CF3 | H | H |
P-99 | CF2CHF2 | CF3 | H | H |
P-100 | CF2CF2CF3 | CF3 | H | H |
P-101 | CCl2CCl2CCl3 | CF3 | H | H |
P-102 | CF2CF2OCH3 | CF3 | H | H |
P-103 | H | H | CF3 | H |
P-104 | CH3 | H | CF3 | H |
P-105 | C2H5 | H | CF3 | H |
P-106 | C3H7 | H | CF3 | H |
P-107 | CClF2 | H | CF3 | H |
P-108 | CCl2F | H | CF3 | H |
P-109 | CF3 | H | CF3 | H |
P-110 | CHF2 | H | CF3 | H |
P-111 | CH2F | H | CF3 | H |
P-112 | CF2CH3 | H | CF3 | H |
P-113 | CCl2CH3 | H | CF3 | H |
P-114 | CF2CF3 | H | CF3 | H |
P-115 | CCl2CCl3 | H | CF3 | H |
P-116 | CF2CHF2 | H | CF3 | H |
P-117 | CF2CF2CF3 | H | CF3 | H |
P-118 | CCl2CCl2CCl3 | H | CF3 | H |
P-119 | CF2CF2OCH3 | H | CF3 | H |
P-120 | H | H | H | CF3 |
P-121 | CH3 | H | H | CF3 |
P-122 | C2H5 | H | H | CF3 |
P-123 | C3H7 | H | H | CF3 |
P-124 | CClF2 | H | H | CF3 |
行F | R1 | R2 | R3 | R4 |
P-125 | CCl2F | H | H | CF3 |
P-126 | CF3 | H | H | CF3 |
P-127 | CHF2 | H | H | CF3 |
P-128 | CH2F | H | H | CF3 |
P-129 | CF2CH3 | H | H | CF3 |
P-130 | CCl2CH3 | H | H | CF3 |
P-131 | CF2CF3 | H | H | CF3 |
P-132 | CCl2CCl3 | H | H | CF3 |
P-133 | CF2CHF2 | H | H | CF3 |
P-134 | CF2CF2CF3 | H | H | CF3 |
P-135 | CCl2CCl2CCl3 | H | H | CF3 |
P-136 | CF2CF2OCH3 | H | H | CF3 |
P-137 | H | H | H | CF3 |
P-138 | CH3 | H | H | CF3 |
P-139 | C2H5 | H | H | CF3 |
P-140 | C3H7 | H | H | CF3 |
P-141 | CClF2 | H | H | CF3 |
P-142 | CCl2F | H | H | CF3 |
P-143 | CF3 | H | H | CF3 |
P-144 | CHF2 | H | H | CF3 |
P-145 | CH2F | H | H | CF3 |
P-146 | CF2CH3 | H | H | CF3 |
P-147 | CCl2CH3 | H | H | CF3 |
P-148 | CF2CF3 | H | H | CF3 |
P-149 | CCl2CCl3 | H | H | CF3 |
P-150 | CF2CHF2 | H | H | CF3 |
P-151 | CF2CF2CF3 | H | H | CF3 |
P-152 | CCl2CCl2CCl3 | H | H | CF3 |
P-153 | CF2CF2OCH3 | H | H | CF3 |
本文所述反应在常用于这类反应的反应容器如搅拌反应器中进行。此外,反应不仅可配置为分批方式,也可配置为连续或半连续方式。通常而言,特定反应将在大气压下进行。然而,反应也可在减压或升高的压力下进行。
在本发明方法中,步骤a)、b)和c)优选在不分离任何中间化合物的条件下进行。更优选步骤a)、b)和c)在单个反应容器内进行。
在本发明方法步骤a)中,合适的碱为碱金属甲醇盐或碱金属乙醇盐,例如锂、钠和钾的甲醇盐以及锂、钠或钾的乙醇盐。优选碱为甲醇钠或乙醇钠,尤其是甲醇钠。在另一个实施方案中,碱溶解于一元C1-C4醇,优选乙醇或甲醇,甚至更优选甲醇中。特别优选溶解于甲醇中的甲醇钠碱。据信碱金属甲醇盐具有合适的碱性,从而能够进行化合物II与化合物IIIa或IIIb之间的反应,并且避免不需要的副反应,确保期望的式I产物的高收率。
在本发明方法步骤a)中,化合物II优选与化合物IIIa混合。
在步骤a)中,化合物II、化合物IIIa或IIIb和碱可以以不同顺序相互接触。但是,通常已经发现有利的是首先加入任选溶解和/或悬浮于溶剂中的化合物II和化合物IIIa或IIIb(混合物),然后将碱加入化合物II和化合物IIIa或IIIb的混合物中。
步骤a)中的反应可在溶剂中进行或本体进行。但是,通常已经发现有利的是使用用于溶解所用碱的溶剂。优选将处于合适溶剂中的碱溶液加入化合物II和化合物IIIa或IIIb的混合物中。
合适的溶剂取决于碱的选择。此处可用的有机溶剂实例包括酰胺如二甲基甲酰胺或N-甲基吡咯烷酮,一元或多元醇如一元C1-C4醇,例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇或叔丁醇,乙二醇或三氟乙醇,或者这些有机溶剂相互的混合物。更优选一元C1-C4醇,尤其是甲醇。
在一个实施方案中,溶剂以脱气形式(即尤其是脱除氧气)使用。溶剂的脱气是已知的并且可以例如通过将溶剂一次或多次冷冻,在减压下融化(以除去溶解/分散在溶剂中的气体),并用惰性气体如氮气或氩气补偿而实现。作为选择或者此外,可以用超声波处理溶剂。
化合物II可商购或者经由标准有机合成方法获得。化合物II的实例优选三氟乙酸甲酯和三氟乙酸乙酯。
化合物IIIa和IIIb可商购或者经由标准有机合成方法获得。
化合物II与化合物IIIa或IIIb的相对量可变化,但在实践中,使用约等摩尔量或者使用稍微摩尔过量的化合物II。化合物II相对于化合物IIIa或IIIb的摩尔比为0.7-3.0通常合适,优选摩尔比为1.0-2.0。
相对于化合物IIIa或IIIb,使用至少等摩尔量的碱;但是实践中通常使用过量的碱。碱相对于化合物IIIa或IIIb的摩尔比为1.0-3.0通常合适,优选摩尔比为1.0-1.5。
步骤a)中的反应可以在宽温度范围内进行,通常为-20℃至150℃。通常使用的温度为35-85℃。优选温度为40-70℃,例如约60℃。
第一反应的时间不受特别限制,通常为10分钟至24小时,优选15分钟至1小时。通常而言,第一反应期为至少30秒。
第一反应期后,将反应混合物用至少一种酸处理。在该步骤b)中,反应混合物和酸可以以不同顺序相互接触。但是,通常已经发现有利的是首先加入任选溶于水中的酸,然后加入反应混合物。
酸是指布朗斯台德酸及其水溶液。优选的布朗斯台德酸为无机酸如氢卤酸、含硫酸、硝酸、含磷酸、硼酸或卤氧酸,尤其是HCl、HBr、HI、HF、H2SO4、甲磺酸、KHSO4、HNO3、HClO4、H3PO4和H3BO3,或者未卤代或卤代的C1-C22链烷羧酸,即未取代的或相互独立地被至多5个卤素如F、Cl或Br取代的C1-C22链烷羧酸,例如甲酸、乙酸、三氟乙酸、丙酸、丁酸、柠檬酸、草酸、己酸、辛酸、癸酸(羊蜡酸)、十二烷酸(月桂酸)、十六烷酸(棕榈酸)或十八烷酸(硬脂酸)。其中,优选非氧化性酸。
通常优选加入酸的水溶液。在酸的水溶液情况下,当使用无机酸时,水溶液中布朗斯台德酸的量优选为5-80重量%,特别优选10-50重量%。
由于HCl、H2SO4、甲酸和乙酸的可得性,因而优选它们,特别优选HCl和H2SO4。
相对于步骤a)中所用碱的量,酸的摩尔量以过量使用。相对于步骤a)中所用碱的量,酸的摩尔比为1.5-4.0通常合适,优选摩尔比为1.5-3.0。
在步骤b)中的反应过程中,酸用于环化化合物II和化合物IIIa或IIIb的缩合产物,从而形成式IV的4-羟基吡喃酮:
其中R1、R2、R3和R4如上所定义。
在本发明方法中,化合物IV原位转化为4-羟基吡啶化合物I而不进行分离。
步骤b)中的反应可以在宽温度范围内进行,通常为-20℃至150℃。通常使用的温度为35-85℃。优选温度为40-70℃,例如约60℃。
第二反应期不受特别限制,通常为30分钟至24小时,优选1小时至5小时。在优选实施方案中,第二反应期不长于2.5小时。
第二反应期后,将反应混合物用至少一种氨源处理。在该步骤c)中,反应混合物和氨源可以以不同顺序相互接触。但是,通常已经发现有利的是首先加入反应混合物,然后加入氨源。
合适的氨源选自氨如氨水溶液或气态氨、卤化铵如氯化铵或溴化铵、羧酸铵如甲酸铵或乙酸铵,以及硫酸铵。由于氨水溶液易于获得,因而优选它。氨水溶液通常浓度为10-40重量%。作为选择,可将气态氨用作氨源。通过将气态氨直接通入反应混合物中或者将其通入反应混合物上的气相中而将气态氨加入反应混合物中。
根据实施方案,在加入氨源之前,将溶剂加入反应混合物中。这些实施方案中优选的是在第一反应期后将酸的水溶液加入反应混合物中,并且在加入氨源之前将水不溶混性溶剂加入反应混合物中以形成两相反应混合物。
合适的水不溶混性溶剂包括羧酸酯如乙酸乙酯、乙酸丙酯或丙酸乙酯,开链醚如乙醚、丙醚、丁醚、甲基异丁基醚和甲基叔丁基醚(MTBE),脂族烃如戊烷、己烷、庚烷和辛烷,以及石油醚,卤代脂族烃如二氯甲烷、三氯甲烷、二氯乙烷和三氯乙烷,脂环族烃如环戊烷和环己烷,以及芳族烃如甲苯、二甲苯、氯苯、二氯苯和三甲基苯。
这类两相溶剂体系适宜地还可包含至少一种相转移催化剂。合适的相转移催化剂是本领域技术人员充分熟知的,并且包括例如带电荷体系,例如有机铵盐如四(C1-C18烷基)铵氯化物或溴化物,例如四甲基铵氯化物或溴化物、四丁基铵氯化物或溴化物、十六烷基三甲基铵氯化物或溴化物、十八烷基三甲基铵氯化物或溴化物、甲基三己基铵氯化物或溴化物、甲基三辛基铵氯化物或溴化物或者苄基三甲基氢氧化铵(Triton B),以及四(C1-C18烷基)氯化物或溴化物如四苯基氯化物或溴化物、[(苯基)m-(C1-C18烷基)n]氯化物或溴化物,其中m为1至3,n为3至1且m与n之和为4,以及吡啶盐如甲基吡啶氯化物或溴化物,和不带电荷体系如冠醚或氮杂冠醚,例如12-冠-4、15-冠-5、18-冠-6、二苯并-18-冠-6或[2,2,2]-穴状配体(222-Kryptofix),环糊精,杯芳烃如[14]-间环芳、杯[4]芳烃和对叔丁基-杯[4]芳烃,和环芳。
步骤c)中的反应可以在宽温度范围内进行,通常为-20℃至150℃。通常使用的温度为15-85℃。优选温度为20-70℃。
加入氨源之后的反应期不受特别限制,通常为30分钟至24小时,优选1小时至5小时。
将所得到的反应混合物后处理,并将化合物I以常规方式,例如通过含水萃取后处理,通过例如在减压下除去溶剂,或通过这些措施的组合分离。进一步提纯可以例如通过结晶、蒸馏或通过层析法实现。
4-羟基吡啶化合物I可用氯化剂处理,从而得到式V的4-氯吡啶:
其中R1、R2、R3和R4如上所定义。
合适的氯化剂包括无机或有机酰基氯,例如三氯化磷、五氯化磷、磷酰氯(三氯氧化磷)、硫酰氯、亚硫酰二氯和光气,优选亚硫酰二氯和磷酰氯。
氯化剂处理可以在不加入稀释剂的条件下本体进行或者在合适稀释剂的存在下进行。合适的稀释剂包括任选卤代的脂族、脂环族或芳族烃,例如苯、甲苯、二甲苯、氯苯、二氯苯、石油醚、己烷、环己烷、甲基环己烷、二氯甲烷、氯仿、四氯甲烷,以及二甲基甲酰胺(DMF),或者它们的混合物并且尤其是甲苯和1,2-二氯苯。
氯化剂处理可任选在合适的反应辅助剂存在下进行。合适的反应辅助剂可以为叔胺如三乙基胺、N,N-二甲基苯胺、吡啶或4-二甲基氨基吡啶,以及催化量的甲酰胺如DMF或N,N-二丁基甲酰胺,或者金属卤化物如氯化镁或氯化锂。
氯化剂处理中,反应温度可在较宽范围内变化。通常而言,反应在0-200℃,优选10-180℃,尤其是30-120℃的温度下进行。
通过以下实施例阐述本发明。
实施例1:
将甲醇钠的甲醇溶液(90g,30重量%,0.5mol)溶于50ml N-甲基吡咯烷酮(NMP)中。逐滴加入4-甲氧基-3-丁烯-2-酮(10.2g,0.1mol)和全氟丙酸甲酯(21.4g,0.12mol),并将该混合物在室温下进一步搅拌48小时。然后将该反应混合物用水水解,并用盐酸(浓)将pH调节至4。用甲基叔丁基醚(MTBE)萃取该产物,并用水洗涤两次。浓缩有机相后,得到19g包含2-全氟乙基吡喃-4-酮的粗产物(HPLC纯度82%,收率:73%)。
实施例2:
将甲醇钠的甲醇溶液(16.2g,30重量%,0.09mol)溶于50ml NMP中。逐滴加入4-甲氧基-3-丁烯-2-酮(6.3g,0.06mol)和2,2,3,3-四氟丙酸甲酯(12.09g,0.08mol),并将该混合物在室温下进一步搅拌48小时。然后将该反应混合物用水水解,并用盐酸(浓)将pH调节至4。用MTBE萃取该产物,并用水洗涤两次。浓缩有机相后,得到6.3g包含2-(2,2,3,3-四氟乙基)-吡喃-4-酮的粗产物(HPLC纯度96%,收率:51%)。
实施例3:
将甲醇钠的甲醇溶液(11.3g,30重量%,0.06mol)溶于50ml NMP中。逐滴加入4-甲氧基-3-丁烯-2-酮(4.2g,0.04mol)和2,2-二氟丙酸乙酯(7.0g,0.05mol),并将该混合物在室温下进一步搅拌48小时。然后将该反应混合物用水水解,并用盐酸(浓)将pH调节至4。用MTBE萃取该产物,并用水洗涤两次。浓缩有机相后,得到4.0g包含2-(2,2-二氟乙基)-吡喃-4-酮的粗产物(HPLC纯度92%,收率:57%)。
实施例4:
将甲醇钠的甲醇溶液(19.7g,30重量%,0.11mol)溶于30ml NMP中。逐滴加入4-甲氧基-3-丁烯-2-酮(2.2g,0.02mol)和2,2,3,3-四氟-3-甲氧基-丙酸甲酯(5.01g,0.03mol),并将该混合物在室温下进一步搅拌48小时。然后将该反应混合物用水水解,并用盐酸(浓)将pH调节至4。用MTBE萃取该产物,并用水洗涤两次。浓缩有机相后,得到5.5g包含2-(2,2,3,3-四氟-3-甲氧基-乙基)-吡喃-4-酮的粗产物(HPLC纯度78%,收率:95%)。
实施例5:
将甲醇钠的甲醇溶液(36.9g,30重量%,0.2mol)溶于150ml NMP中。逐滴加入4-甲氧基-3-丁烯-2-酮(13.6g,0.14mol)和全氟丁酸乙酯(39.5g,0.16mol),并将该混合物在室温下进一步搅拌48小时。然后将该反应混合物用水水解,并用盐酸(浓)将pH调节至4。用MTBE萃取该产物,并用水洗涤两次。浓缩有机相后,得到13g包含2-全氟丙基吡喃-4-酮的粗产物(HPLC纯度93%,收率:33%)。
实施例6:
将4,4-二甲氧基丁酮(20.0g,0.13mol)和三氟乙酸乙酯(28.7g,0.2mol)加入三颈烧瓶中。在0.5小时内加入甲醇钠的甲醇溶液(30重量%,38ml,0.2mol),并且将该混合物在60℃下进一步搅拌0.5小时。然后加入盐酸(10重量%,146ml,0.400mol)。该反应混合物变为深红色。将该反应混合物在60℃至40℃下搅拌约2.5小时。
然后在40-50℃下于10分钟内加入氨水(25重量%,45.3ml,0.67mol),并且将该混合物在50℃至22℃下搅拌约18小时。
通过旋转蒸发由该反应混合物除去甲醇。将200g水和200g MTBE加入该残余物中,将该混合物搅拌15分钟。分离有机相并用50g MTBE萃取水相。将合并的有机相蒸发,得到深色油状物(20.8g),其包含85.8重量%的4-羟基-2-三氟甲基吡啶(收率:82%)。
实施例7:
将4-羟基-2-三氟甲基吡啶(6.4g,39mmol)溶于1,2-二氯苯(64g)中。将亚硫酰二氯(23.2g,195mmol)和DMF(10滴)加入该反应混合物中,然后将该反应混合物加热至70-80℃。约2小时后,反应完成,在升高的温度下除去过量的亚硫酰二氯。在减压下蒸馏(50℃,15毫巴)所需产物,得到4-氯-2-三氟甲基-吡啶(6.5g,36mmol,收率:92%)。如果需要的话,用含水后处理除去剩余的DMF。
Claims (18)
1.一种制备式I的4-羟基吡啶的方法:
其中
R1为氢、C1-C4烷基、C1-C4卤代烷基、芳基或杂芳基,其中后提到的两个基团未被取代或者被1、2、3或4个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;
R2、R3和R4独立地为氢、C1-C4烷基、C1-C4卤代烷基、NR5R6或芳基,其中所述芳基未被取代或者被1、2、3或4个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;
或者基团R3和R4与它们所键合的碳原子一起形成3、4、5、6或7元饱和、部分不饱和或最大程度不饱和的碳环或者包含1、2或3个选自O、S和N的杂原子作为环成员的3、4、5、6或7元饱和、部分不饱和或最大程度不饱和的杂环,其中所述碳环或杂环未被取代或者被1、2、3或4个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基的取代基取代;
R5为氢、C1-C4烷基或C1-C4卤代烷基;
R6为氢、C1-C4烷基、C1-C4卤代烷基、苯基和苯基-C1-C4烷基;
或者R5和R6一起形成线性C4-或C5-亚烷基桥或基团-CH2CH2OCH2CH2-或-CH2CH2NR7CH2CH2-;并且
R7为氢或C1-C4烷基;
所述方法包括:
a)将式II化合物:
其中R1如上所定义;
X为卤素或C1-C4烷氧基;
与式IIIa化合物:
其中R2、R3、R4如上所定义;
Y独立地为卤素或C1-C4烷氧基;
或者式IIIa化合物中的两个基团Y一起形成基团-O-(CH2)n-O-,其中链烷二基结构部分-(CH2)n-未被取代或者被1、2或3个选自卤素和C1-C4烷基的取代基取代;并且
n为2、3或4;
Y独立地为卤素或C1-C4烷氧基;
以及至少一种选自碱金属甲醇盐和碱金属乙醇盐的碱混合,以形成反应混合物;
b)在步骤a)之后,将所述反应混合物用至少一种酸处理;以及
c)在步骤b)之后,将所述反应混合物用至少一种氨源处理。
2.根据权利要求1所述的方法,其中所述碱选自碱金属甲醇盐。
3.根据权利要求2所述的方法,其中所述碱为甲醇钠。
4.根据权利要求1所述的方法,其中将所述碱溶于一元C1-C4醇中。
5.根据权利要求2所述的方法,其中将所述碱溶于一元C1-C4醇中。
6.根据权利要求3所述的方法,其中将所述碱溶于一元C1-C4醇中。
7.根据权利要求4所述的方法,其中所述一元C1-C4醇为甲醇。
8.根据权利要求5所述的方法,其中所述一元C1-C4醇为甲醇。
9.根据权利要求6所述的方法,其中所述一元C1-C4醇为甲醇。
10.根据权利要求1-9中任一项所述的方法,其中步骤a)、b)和c)在不分离任何中间化合物下进行。
11.根据权利要求1-9中任一项所述的方法,其中所述酸选自无机酸。
12.根据权利要求1-9中任一项所述的方法,其中所述氨源选自氨水溶液、卤化铵、羧酸铵和硫酸铵。
13.根据权利要求1-9中任一项所述的方法,其中R1为氢、C1-C4烷基或C1-C4卤代烷基。
14.根据权利要求13所述的方法,其中R1为C1-C4全卤代烷基。
15.根据权利要求1-9中任一项所述的方法,其中R2、R3、R4为氢、C1-C4烷基或C1-C4卤代烷基。
16.根据权利要求15所述的方法,其中R2、R3、R4为氢。
17.根据权利要求1-9中任一项所述的方法,额外包括将化合物I用氯化剂处理,以得到式V的4-氯吡啶:
其中R1、R2、R3和R4如权利要求1中所定义。
18.根据权利要求17所述的方法,其中所述氯化剂为亚硫酰二氯或磷酰氯。
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