CN113527191B - Preparation method of 2,3-dichloro-5-trifluoromethylpyridine - Google Patents
Preparation method of 2,3-dichloro-5-trifluoromethylpyridine Download PDFInfo
- Publication number
- CN113527191B CN113527191B CN202010277405.5A CN202010277405A CN113527191B CN 113527191 B CN113527191 B CN 113527191B CN 202010277405 A CN202010277405 A CN 202010277405A CN 113527191 B CN113527191 B CN 113527191B
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- CN
- China
- Prior art keywords
- formula
- dichloro
- trifluoromethylpyridine
- solvent
- compound
- Prior art date
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- ABNQGNFVSFKJGI-UHFFFAOYSA-N 2,3-dichloro-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=C(Cl)C(Cl)=C1 ABNQGNFVSFKJGI-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 20
- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 230000009471 action Effects 0.000 claims abstract description 14
- -1 oxalic acid diester Chemical class 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000020477 pH reduction Effects 0.000 claims abstract description 9
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 6
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000006482 condensation reaction Methods 0.000 claims description 16
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 10
- MMVVKVXNCHNBKA-UHFFFAOYSA-N 3,3,3-trifluoro-2-methyl-1-nitroprop-1-ene Chemical group FC(F)(F)C(C)=C[N+]([O-])=O MMVVKVXNCHNBKA-UHFFFAOYSA-N 0.000 abstract description 32
- OOFGZDCVYPUSBJ-UHFFFAOYSA-N 3-hydroxy-5-(trifluoromethyl)-1h-pyridin-2-one Chemical compound OC1=CC(C(F)(F)F)=CNC1=O OOFGZDCVYPUSBJ-UHFFFAOYSA-N 0.000 abstract description 26
- 239000002994 raw material Substances 0.000 abstract description 14
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 8
- 238000003682 fluorination reaction Methods 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- YZZGJHDTYZOSIH-UHFFFAOYSA-N 2,3-dichloro-5-methylpyridine Chemical compound CC1=CN=C(Cl)C(Cl)=C1 YZZGJHDTYZOSIH-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- SKCNYHLTRZIINA-UHFFFAOYSA-N 2-chloro-5-(chloromethyl)pyridine Chemical compound ClCC1=CC=C(Cl)N=C1 SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XVBWGQSXLITICX-UHFFFAOYSA-N 2,3-dichloro-5-(trichloromethyl)pyridine Chemical compound ClC1=CC(C(Cl)(Cl)Cl)=CN=C1Cl XVBWGQSXLITICX-UHFFFAOYSA-N 0.000 description 2
- JFZJMSDDOOAOIV-UHFFFAOYSA-N 2-chloro-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)N=C1 JFZJMSDDOOAOIV-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000002587 enol group Chemical group 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LNHMAMSDSKYNSS-UHFFFAOYSA-N 1,1,1-trifluoro-2-methyl-3-nitropropan-2-ol Chemical compound FC(F)(F)C(O)(C)C[N+]([O-])=O LNHMAMSDSKYNSS-UHFFFAOYSA-N 0.000 description 1
- UPWAAFFFSGQECJ-UHFFFAOYSA-N 2,6-dichloro-3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)N=C1Cl UPWAAFFFSGQECJ-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000005780 Fluazinam Substances 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- XCLXGCQTGNGHJQ-UHFFFAOYSA-N ethyl 2-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyphenoxy]propanoate Chemical group C1=CC(OC(C)C(=O)OCC)=CC=C1OC1=NC=C(C(F)(F)F)C=C1Cl XCLXGCQTGNGHJQ-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- UZCGKGPEKUCDTF-UHFFFAOYSA-N fluazinam Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=C(Cl)C([N+]([O-])=O)=C1NC1=NC=C(C(F)(F)F)C=C1Cl UZCGKGPEKUCDTF-UHFFFAOYSA-N 0.000 description 1
- RYLHNOVXKPXDIP-UHFFFAOYSA-N flufenoxuron Chemical compound C=1C=C(NC(=O)NC(=O)C=2C(=CC=CC=2F)F)C(F)=CC=1OC1=CC=C(C(F)(F)F)C=C1Cl RYLHNOVXKPXDIP-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- MFSWTRQUCLNFOM-UHFFFAOYSA-N methyl 2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoate Chemical group C1=CC(OC(C)C(=O)OC)=CC=C1OC1=NC=C(C(F)(F)F)C=C1Cl MFSWTRQUCLNFOM-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000010626 work up procedure Methods 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
- C07D213/61—Halogen atoms or nitro radicals
-
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Abstract
The invention provides a preparation method of 2, 3-dichloro-5-trifluoromethylpyridine. The method comprises the steps of condensing and acidifying 1, 1-trifluoroacetone and nitromethane under the action of alkali to obtain 1-nitro-2-trifluoromethylpropylene, condensing 1-nitro-2-trifluoromethylpropylene and oxalic acid diester under the action of alkali, carrying out reduction-cyclization reaction and acidification on the obtained reaction liquid without separation in the presence of a catalyst to obtain 2, 3-dihydroxy-5-trifluoromethylpyridine, and carrying out chlorination reaction on the 2,3-dichloro-5-trifluoromethylpyridine and a chlorinated reagent to obtain the 2, 3-dichloro-5-trifluoromethylpyridine. The method has the advantages of low price and easy obtainment of raw materials, high reaction selectivity of each step, no need of using special equipment for high-temperature chlorination and high-temperature fluorination, easy operation of technological process, high yield and purity of target products and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of 2,3-dichloro-5-trifluoromethylpyridine, belonging to the technical field of chemistry and chemical engineering.
Background
2,3-dichloro-5-trifluoromethylpyridine (I) of formula C 6 H 2 Cl 2 F 3 N, having the name 2, 3-dichoro-5-trifluoromethylpyridine and the CAS number [69045-84-7 ]]The compound is an important intermediate, can be used for preparing pesticides such as haloxyfop-methyl, fluazinam, pyrafluazuron, flufenoxuron, haloxyfop-ethyl, and flupyraclostrobin and developing novel medicines and dyes, and has important significance for researching and optimizing the preparation method of the 2,3-dichloro-5-trifluoromethyl pyridine and developing downstream products thereof.
The structural formulas of 2,3-dichloro-5-trifluoromethylpyridine (I) and its major downstream marketable products are as follows:
at present, the preparation method of 2,3-dichloro-5-trifluoromethylpyridine mainly focuses on the chlorination and fluorination of 3-methylpyridine or 3-methylpyridine substitutes.
In the prior art, 3-methylpyridine is used as a raw material to prepare 2,3-dichloro-5-trifluoromethylpyridine in a special reactor by one-step high-temperature substitution (350-450 ℃) with chlorine, hydrogen fluoride and a catalyst. However, the high-temperature substitution reaction has poor selectivity, a large amount of byproducts, a large amount of tar, difficult separation and purification of products, low product purity of only about 95 percent, product yield of only 40 percent, special equipment and no industrialization favor. Chinese patent CN101062914A takes 2, 3-dichloro-5-methylpyridine as raw material, chloridizes under the action of organic solvent and catalyst, then prepares 2, 3-dichloro-5-trichloromethylpyridine through removing organic solvent, crystallization and centrifugation, and prepares 2,3-dichloro-5-trifluoromethylpyridine through high-temperature high-pressure fluoro, with the total yield of 85%. The price of the raw material 2, 3-dichloro-5-methylpyridine is high, special equipment is needed for high-temperature and high-pressure hydrofluoride fluorination (160-185 ℃ and 65-85 atmospheric pressure), the cost of the product is not reduced, and the industrial production value is not high.
Chinese patent CN104557683B uses 2-chloro-5-chloromethylpyridine as raw material, prepares 2, 3-dichloro-5-trichloromethylpyridine by high-temperature chlorination under the action of catalyst, and then prepares 2,3-dichloro-5-trifluoromethylpyridine by high-temperature high-pressure fluorination, with a total yield of 63.2%. The method has the advantages that the price of the raw material 2-chloro-5-chloromethylpyridine is high, the chlorination temperature is as high as 275 ℃, the chlorination time is long (60 hours), special equipment is needed for high-temperature and high-pressure fluorination of hydrogen fluoride (160-185 ℃,65-85 atmospheric pressure), and the method is not beneficial to reduction of product cost and industrialization. WO2019109936 uses 2-chloro-5-trifluoromethylpyridine as a raw material, and reacts with chlorine gas under the action of a catalyst at the temperature of 100-150 ℃ and the pressure of 0.5-5.0 MPa to perform 3-site chlorination to obtain the 2, 3-dichloro-5-trifluoromethylpyridine.
The raw materials of 3-methylpyridine, 2-chloro-5-chloromethylpyridine, 2, 3-dichloro-5-methylpyridine or 2-chloro-5-trifluoromethylpyridine used in the above routes are high in price, the above routes all involve high-temperature chloro and high-temperature fluoro, special equipment is required, the operation conditions are harsh, and the defects of more side reactions exist, the 2-position and 6-position of pyridine ring are high in activity, the high-temperature chloro and high-temperature fluoro conditions are difficult to selectively carry out 3-position substitution to keep 6-position reaction inertia, and in addition, the high-temperature chloro and high-temperature fluoro have rearrangement of chlorine atoms or fluorine atoms, so that the separation and purification of products are difficult.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel preparation method of 2, 3-dichloro-5-trifluoromethylpyridine.
The technical problems to be solved by the invention include: the 2,3-dichloro-5-trifluoromethylpyridine prepared by the prior art has high initial raw material price, harsh high-temperature chlorination and high-temperature fluorination conditions and more side reactions, is difficult to selectively carry out 3-position substitution and keep 6-position reaction inertia, has high requirements on equipment and operation, and is difficult to industrially popularize.
The method takes the 1-nitro-2-trifluoromethyl propylene as an initial raw material, is cheap and easily obtained, has simple and convenient operation method, is easy to realize, is safe and environment-friendly, has small waste water amount, low cost, high yield and selectivity and few byproducts, and is suitable for industrial production.
Description of terms:
a compound of formula II: 1-nitro-2-trifluoromethylpropene;
a compound of formula III: 4-trifluoromethyl-5-nitro-2-MO substituent-2, 4-dienoic valerate;
a compound of formula IV: 2, 3-dihydroxy-5-trifluoromethylpyridine;
a compound of formula I: 2, 3-dichloro-5-trifluoromethylpyridine.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a method for preparing 2,3-dichloro-5-trifluoromethylpyridine, comprising the steps of:
(1) Condensing 1, 1-trifluoroacetone and nitromethane in a solvent A under the action of an alkali A, and then acidifying to obtain a compound shown in a formula II;
the alkali A is one or a combination of sodium hydroxide, potassium hydroxide and lithium hydroxide;
the solvent A is one or a combination of water, C1-C4 low-carbon alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether or toluene;
(2) Condensing a compound shown in a formula II and oxalic acid diester in a solvent B under the action of alkali B to obtain a reaction solution containing a compound shown in a formula III, directly carrying out reduction-cyclization reaction on the compound shown in the formula III in the presence of a catalyst without separation, and then acidifying to obtain a compound shown in a formula IV;
wherein in the structural formula of the compound shown in the formula III, R is methyl, ethyl, propyl, isopropyl, tert-butyl or other C 4 H 9 Butyl, M is K, na or Li;
the alkali B is sodium hydroxide solid, potassium hydroxide solid, lithium hydroxide solid, sodium methoxide solid, sodium ethoxide solid, sodium tert-butoxide solid, sodium methoxide methanol solution or sodium ethoxide ethanol solution;
the solvent B is one or a combination of C1-C4 low-carbon alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether or toluene;
(3) In a solvent C, carrying out chlorination reaction on a compound shown in the formula IV and a chlorinated reagent to obtain 2,3-dichloro-5-trifluoromethylpyridine (I);
the solvent C is one or the combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, chlorinated reagent or chlorobenzene.
According to the invention, in step (1), the mass ratio of the solvent A to the 1, 1-trifluoroacetone is (2-10): 1.
According to a preferred embodiment of the invention, in step (1), the molar ratio of the base A to 1, 1-trifluoroacetone is (1.0-1.5): 1. The base A is added as a solution configured as solvent A when used.
According to a preferred embodiment of the invention, in step (1), the molar ratio of nitromethane to 1, 1-trifluoroacetone is (1.0-1.5): 1.
Preferably, according to the invention, in step (1), the condensation reaction temperature is-40 to 40 ℃; preferably, the condensation reaction temperature is-10-10 ℃. The condensation reaction time is 0.5-5 hours; the condensation reaction time is preferably 2 to 3 hours.
According to a preferred embodiment of the invention, in step (1), hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid is used for the acidification, and the molar ratio of the acid to 1, 1-trifluoroacetone is (0.4-1.5): 1. The concentration of the acid is 20-50% by mass.
According to the invention, in the step (2), the mass ratio of the solvent B to the compound of the formula II is (1-15): 1.
In the solvent A in the step (1) and the solvent B in the step (2), the C1-C4 lower alcohol is one or a combination of methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol and n-butanol.
According to a preferred embodiment of the invention, in step (2), the molar ratio of the base B to the compound of the formula II is (1.0-1.5): 1. The metal M in the compound in the formula III in the step (2) is introduced by the base B, the 3-methylene has higher acidity and is in an enol form under a reaction system, and the metal M and the base B form an alcohol base.
According to the invention, in step (2), the molar ratio of the oxalic acid diester to the compound of formula II is (1.0-1.5): 1.
Preferably, according to the invention, in step (2), the condensation reaction temperature is 10-80 ℃; preferably, the condensation reaction temperature is 20-40 ℃. The condensation reaction time is 1-5 hours; preferably, the condensation reaction time is 2 to 3 hours.
According to the present invention, preferably, the catalyst in step (2) is composed of a main catalyst and a cocatalyst, wherein the main catalyst is a palladium-carbon catalyst or a Raney nickel catalyst; more preferably, the mass of the palladium-carbon catalyst is 0.5 to 10 percent of that of the compound shown in the formula II, and the mass of the Raney nickel catalyst is 5 to 25 percent of that of the compound shown in the formula II; most preferably, the mass of the palladium-carbon catalyst is 1 to 5 percent of the mass of the compound of the formula II, and the mass of the Raney nickel catalyst is 10 to 15 percent of the mass of the compound of the formula II; the cocatalyst is tertiary amine, pyridine compound, trisubstituted phosphine, thiophenol or thioether, preferably triethylamine, tri-n-butylamine, pyridine, 4-dimethylaminopyridine, triphenylphosphine or diphenyl sulfide, and the mass of the cocatalyst is 0.1-0.5% of that of the compound shown in the formula II; preferably 0.3% to 0.4%.
According to the present invention, it is preferable that, in the step (2), the reduction-cyclization reaction temperature is 20 to 100 ℃, and the hydrogen pressure is 0.1 to 0.5MPa; further preferably, the reduction-cyclization reaction temperature is 30-60 ℃, and the hydrogen pressure is 0.2-0.4MPa. The reduction-cyclization reaction time is 3 to 10 hours; further preferably, the reduction-cyclization reaction time is 4 to 8 hours.
According to a preferred embodiment of the invention, in step (2), hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid is used for the acidification, and the molar ratio of the acid to the compound of formula II is (0.4-1.5): 1. The concentration of the acid is preferably 20 to 50 mass percent.
According to the invention, in the step (3), the mass ratio of the solvent C to the compound of the formula IV is preferably (0-10): 1.
According to the invention, preferably, in the step (3), the chlorinated reagent is one or a combination of more than two of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, diphosgene or triphosgene; the mol ratio of the chlorinated reagent to the compound shown in the formula IV is (0.5-10) to 1; preferably, the molar ratio of the chlorinating reagent to the compound of formula IV is (1.0-5.0): 1. The chlorinating agent may be used in excess, and in excess, the chlorinating agent may act as a solvent.
According to the present invention, it is preferred that, in the step (3), the chlorination reaction temperature is 40 to 130 ℃; preferably, the chlorination reaction temperature is 50 to 110 ℃, most preferably 60 to 80 ℃. The chlorination reaction time is 2 to 18 hours, preferably 4 to 8 hours.
In the process of the invention, the product work-up of steps (1), (2) and (3) is carried out according to the prior art.
The process of the present invention is depicted as scheme 1 below:
wherein in the structural formula of the compound shown in the formula III, R is methyl, ethyl, propyl, isopropyl, tert-butyl or other C 4 H 9 Butyl, M is K, na or Li.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel preparation method of 2,3-dichloro-5-trifluoromethylpyridine, which comprises the steps of condensing 1, 1-trifluoroacetone and nitromethane under the action of strong alkali, acidifying to obtain 1-nitro-2-trifluoromethylpropylene, condensing 1-nitro-2-trifluoromethylpropylene and oxalic acid diester under the action of alkali, carrying out reduction-cyclization reaction and acidification on the obtained reaction liquid in the presence of a catalyst to obtain 2, 3-dihydroxy-5-trifluoromethylpyridine, and carrying out chlorination on the 2, 3-dihydroxy-5-trifluoromethylpyridine and a chlorinated reagent to obtain the 2, 3-dichloro-5-trifluoromethylpyridine.
2. The mechanism of action of the invention is different from the methods of the prior documents which utilize 3-substituted pyridine or 2, 3-disubstituted pyridine to carry out high-temperature chlorination or fluorination, and the 6-position hydrogen atom of the 3-substituted pyridine or the 2, 3-disubstituted pyridine is easy to be chlorinated or fluorinated, so that 6-position substituted isomer is generated. The invention utilizes 1, 1-trifluoroacetone and nitromethane to condense and acidify under the action of strong alkali to obtain 1-nitro-2-trifluoromethylpropylene, methyl connected with a carbon-carbon double bond in the 1-nitro-2-trifluoromethylpropylene has higher activity under the activation of nitro, can specifically form carbanions under the action of alkali, then condenses with oxalic acid diester under the action of alkali, exists in a stable enol form (shown in formula III) in a system after condensation, the obtained reaction liquid carries out reduction-cyclization reaction in the presence of a catalyst, under the condition, only nitro can be reduced into amino, and a cocatalyst can participate in 1, 4-addition of unsaturated ester to obtain a conformation which is favorable for completely promoting amidation cyclization of amino and ester group, an intermediate product for reducing nitro into amino is not accumulated, the low concentration is favorable for intramolecular pyridine cyclization, and guarantee is provided for obtaining 2, 3-dihydroxy-5-trifluoromethylpyridine with high yield and high purity. Then the 2, 3-dihydroxy-5-trifluoromethyl pyridine and the chlorinated reagent can be chlorinated with high selectivity under mild conditions to react to obtain the 2,3-dichloro-5-trifluoromethyl pyridine, the generation of 6-chloro isomers is thoroughly avoided from the aspect of reaction design, and the purity of the obtained product is high.
3. The raw materials used in the invention are cheap and easy to obtain, the initial raw material 1, 1-trifluoroacetone in the invention is about 1.8 ten thousand/ton, while the initial raw material 3-methylpyridine in the existing literature method is 1.4-1.5 times of 1, 1-trifluoroacetone, and the price of 2, 3-dichloro-5-methylpyridine is 3-4 times of 1, 1-trifluoroacetone.
4. The technological process of the invention is easy to operate, does not need to utilize special equipment to carry out high-temperature chlorination and high-temperature fluorination reaction, does not have 6-chloro byproducts such as 2, 6-dichloro-3-trifluoromethylpyridine and the like, has low cost of target products and high yield and purity, can achieve more than 85 percent of total yield in three steps, is 10 to 22 percent higher than that in the prior art, and is suitable for industrial production.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is given by weight unless otherwise specified. The yields in the examples are all molar yields.
Example 1: preparation of 1-nitro-2-trifluoromethylpropene (II)
Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 350 g of methanol, 61.04 g (1.0 mol) of nitromethane and 112.05 g (1.0 mol) of 1, 1-trifluoroacetone were charged, cooled, the temperature was maintained at 0 to 5 ℃ and 150 g (1.13 mol) of a 30% aqueous solution of sodium hydroxide was added dropwise over 1 hour, and thereafter, the reaction was stirred at 10 to 15 ℃ for 2 hours. The resulting reaction solution was added to a mixture of 150 g (1.23 mol) of 30% hydrochloric acid and 150 g of methylene chloride, the layers were separated, and the aqueous phase was extracted twice with 50 g of methylene chloride each time. After combining the organic phases, washing was carried out once with 30 g of saturated aqueous sodium chloride solution. After the dichloromethane and the solvent are recovered by organic phase distillation, the mixture is rectified under reduced pressure (70-80 ℃/5-7 mmHg) to obtain 145.1 g of 1-nitro-2-trifluoromethyl propylene (II), the gas phase purity is 99.7 percent, and the yield is 93.6 percent.
The nuclear magnetic data of the product are as follows:
1 H NMR(CDCl 3 ,δ,ppm)：
1.66(s，3H)，7.02(s，1H)。
example 2: preparation of 1-nitro-2-trifluoromethylpropene (II)
Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 350 g of methanol, 85.5 g (1.4 mol) of nitromethane and 112.05 g (1.0 mol) of 1, 1-trifluoroacetone were charged, cooled, the temperature was maintained at 5 to 10 ℃ and 150 g (1.13 mol) of a 30% sodium hydroxide methanol solution was added dropwise over 1 hour, and thereafter, the reaction was stirred at 10 to 15 ℃ for 2 hours. The resulting reaction solution was added to a mixture of 150 g (1.23 mol) of 30% hydrochloric acid and 150 g of methylene chloride, the layers were separated, and the aqueous phase was extracted twice with 20 g of methylene chloride each time. After combining the organic phases, washing was carried out once with 30 g of saturated aqueous sodium chloride solution. After the dichloromethane and the solvent are recovered by organic phase distillation, 147.5 g of 1-nitro-2-trifluoromethylpropene (II) is obtained by reduced pressure distillation (70-80 ℃/5-7 mmHg), the gas phase purity is 99.6 percent, and the yield is 95.1 percent.
Example 3: preparation of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV)
Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 200 g of methanol, 43.8 g (0.3 mol) of diethyl oxalate, 48.2 g (0.25 mol) of 28% sodium methoxide methanol solution were charged, cooled, kept at 10 to 20 ℃ and 31.0 g (0.2 mol) of 1-nitro-2-trifluoromethylpropene (II) obtained in example 1 was added dropwise over about 2 hours, and thereafter, the mixture was stirred at 20 to 25 ℃ for 1 hour. Transferring the obtained reaction liquid to a 500 ml stainless steel pressure kettle, adding 0.7 g of 5% palladium carbon and 0.1 g of triphenylphosphine, replacing 3 times by nitrogen, then carrying out catalytic hydrogenation reaction at 40-45 ℃ for 3 hours with the pressure of hydrogen gas being 0.2-0.3MPa, cooling to room temperature after the reduction-cyclization reaction is finished, adding 100 g of water, filtering and separating out the palladium carbon, acidifying the filtrate by 36.5 g (0.3 mol) of 30% hydrochloric acid, filtering and drying to obtain 33.0 g of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV), wherein the yield is 92.3%, and the liquid phase purity is 99.7%.
The nuclear magnetic data of the product are as follows:
1 H NMR(DMSO,δ,ppm)：
4.17(s，2H)，7.11(s，1H)，7.32(s，1H)。
example 4: preparation of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV)
Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 200 g of methanol, 29.5 g (0.25 mol) of dimethyl oxalate and 48.2 g (0.25 mol) of 28% sodium methoxide methanol solution were charged, cooled, maintained at 10 to 20 ℃ and 31.0 g (0.2 mol) of 1-nitro-2-trifluoromethylpropene (II) obtained in example 2 was added dropwise over about 2 hours, and thereafter, the mixture was stirred at 20 to 25 ℃ for 1 hour. Transferring the obtained reaction liquid into a 500 ml stainless steel pressure kettle, adding 0.7 g of 5% palladium carbon and 0.1 g of triphenylphosphine, replacing 3 times by nitrogen, then carrying out catalytic hydrogenation reaction at 40-45 ℃ for 3 hours with the pressure of hydrogen gas being 0.2-0.3MPa, cooling to room temperature after the hydrogenation reaction is finished, adding 100 g of water, filtering and separating out the palladium carbon, acidifying the filtrate by 36.5 g (0.3 mol) of 30% hydrochloric acid, filtering and drying to obtain 32.8 g of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV), wherein the yield is 91.6% and the liquid phase purity is 99.6%.
Example 5: preparation of 2,3-dichloro-5-trifluoromethylpyridine (I)
Into a 500 ml four-necked flask equipped with a thermometer, stirring and reflux condenser were charged 70 g of phosphorus oxychloride, 17.9 g (0.1 mol) of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV) prepared in example 3, 52.0 g (0.25 mol) of phosphorus pentachloride, and the mixture was stirred at 70 to 75 ℃ for reaction for 8 hours, followed by vacuum distillation to recover the excess phosphorus oxychloride, and the residue was slowly poured into 200 g of ice water, sufficiently stirred, then neutralized with 40wt% aqueous sodium hydroxide solution to a pH of 8 to 9, extracted three times with methylene chloride, 100 g each time, and the organic phases were combined, washed with 30 g of saturated brine, then dried with 5.0 g of anhydrous sodium sulfate, rotary-distilled to remove the solvent, and rectified under reduced pressure (60 to 70 ℃/10 to 15 mmHg) to obtain 20.5 g of 2,3-dichloro-5-trifluoromethylpyridine (I), with a yield of 94.9% and a gas phase purity of 99.9%.
The nuclear magnetic data of the product are as follows:
1 H NMR(CDCl 3 ,δ,ppm)：
7.96(s，1H)，8.66(s，1H)。
example 6: preparation of 2,3-dichloro-5-trifluoromethylpyridine (I)
Into a 500 ml four-necked flask equipped with a thermometer, stirring and reflux condenser were charged 150 g of 1, 2-dichloroethane, 17.9 g (0.1 mol) of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV) prepared in example 4, 52.0 g (0.25 mol) of phosphorus pentachloride, and the reaction was carried out with stirring at 60 to 65 ℃ for 8 hours, then the residue was slowly poured into 200 g of ice water, followed by stirring well, then neutralized with 40wt% aqueous sodium hydroxide solution at pH of 8 to 9, layering, three times with 1, 2-dichloroethane for 50 g each, and the organic phases were combined, washed with 30 g of saturated common salt, then dried with 5.0 g of anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and rectification under reduced pressure (60 to 70 mmHg, 10 to 15) was carried out to give 21.1 g of 2,3-dichloro-5-trifluoromethylpyridine (I), yield 97.7%, and purity of the gas phase was 99.9%.
Comparative example 1: preparation of 1-nitro-2-trifluoromethylpropene (II)
A500 ml four-necked flask equipped with a stirrer and a thermometer was charged with 350 g of methanol, 61.04 g (1.0 mol) of nitromethane, 112.05 g (1.0 mol) of 1, 1-trifluoroacetone, cooled, maintained at 0 to 5 ℃ and 150 g (1.13 mol) of a 30% aqueous solution of sodium hydroxide was added dropwise over 1 hour, and after that, the reaction was stirred at 10 to 15 ℃ for 2 hours. To the reaction solution obtained was added a mixture of 150 g (1.23 mol) of 30% hydrochloric acid and 150 g of methylene chloride, the layers were separated, and the aqueous phase was extracted twice with 50 g of methylene chloride each time. After combining the organic phases, washing was carried out once with 30 g of saturated aqueous sodium chloride solution. After the dichloromethane and the solvent are recovered by organic phase distillation, 101.2 g of 1-nitro-2-trifluoromethylpropene (II) is obtained by reduced pressure distillation (70-80 ℃/5-7 mmHg), the gas phase purity is 96.3 percent, and the yield is 65.3 percent.
As can be seen from comparative example 1, after the reaction is completed, the acidification mode is crucial to the product yield, and if the acid is added into the reaction system, the system can not keep sufficient acidity before the acid is completely added, which is not beneficial to the elimination of water, the product yield is low, and more 1-nitro-2-trifluoromethyl-2-propanol is generated. The reaction liquid is added into acid for acidification, so that the acidity in the acidification process is ensured, the elimination of water is facilitated, and the yield of the final product is influenced significantly.
Comparative example 2: preparation of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV)
Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 200 g of methanol, 43.8 g (0.3 mol) of diethyl oxalate, 48.2 g (0.25 mol) of 28% sodium methoxide methanol solution and 31.0 g (0.2 mol) of 1-nitro-2-trifluoromethylpropene (II) obtained by the method of example 1 were charged, and the mixture was stirred and reacted at 20 to 25 ℃ for 1 to 2 hours until the compound II was converted to a satisfactory level. Transferring the obtained reaction liquid to a 500 ml stainless steel pressure kettle, adding 0.7 g of 5% palladium carbon and 0.1 g of triphenylphosphine, replacing 3 times by nitrogen, then carrying out catalytic hydrogenation reaction at 40-45 ℃ for 3 hours with the pressure of hydrogen gas being 0.2-0.3MPa, cooling to room temperature after the hydrogenation reaction is finished, adding 100 g of water, filtering and separating out the palladium carbon, acidifying the filtrate by 36.5 g (0.3 mol) of 30% hydrochloric acid, filtering and drying to obtain 22.9 g of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV), wherein the yield is 63.9% and the liquid phase purity is 96.2%.
As can be seen from comparative example 2, the manner of feeding the compound of formula II is critical, and if the compound of formula II is fed at once, the concentration of the compound of formula II in the system is high, and a reaction by-product of two molecules of the compound of formula II and one molecule of the oxalic acid diester is liable to occur, which cannot undergo reduction-cyclization to give a product containing a pyridine ring, and the yield and purity of the product are lowered.
Comparative example 3: preparation of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV)
Into a 500 ml four-necked flask equipped with a stirrer and a thermometer, 200 g of methanol, 43.8 g (0.3 mol) of diethyl oxalate, 48.2 g (0.25 mol) of 28% sodium methoxide methanol solution, and 31.0 g (0.2 mol) of 1-nitro-2-trifluoromethylpropene (II) obtained by the method of example 2 were charged, and the mixture was stirred and reacted at 20 to 25 ℃ for 1 to 2 hours until the compound II was converted to a satisfactory one. Transferring the obtained reaction liquid to a 500 ml stainless steel pressure kettle, adding 0.7 g of 5% palladium carbon, replacing with nitrogen for 3 times, then carrying out catalytic hydrogenation reaction at 40-45 ℃ for 3 hours under the condition that the pressure of hydrogen charging pressure is 0.2-0.3MPa, cooling to room temperature after the hydrogenation reaction is finished, adding 100 g of water, filtering and separating out the palladium carbon, acidifying the filtrate with 36.5 g (0.3 mol) of 30% hydrochloric acid, filtering and drying to obtain 16.3 g of 2, 3-dihydroxy-5-trifluoromethylpyridine (IV), wherein the yield is 45.5%, and the liquid phase purity is 98.2%.
As can be seen from comparative example 3, the addition mode of the cocatalyst (triphenylphosphine) is very important for the yield of the target product, the cocatalyst can participate in 1, 4-addition of unsaturated ester while reducing nitro to amino, so that conformation which is favorable for completely promoting amino and ester to carry out amidation cyclization is obtained, intramolecular pyridine cyclization reaction is facilitated, and guarantee is provided for obtaining 2, 3-dihydroxy-5-trifluoromethylpyridine with high yield and high purity. If no cocatalyst triphenylphosphine is added, the nitro is reduced into amino, the obtained amino is connected to a carbon-carbon double bond, and the conformation that the amino and the unsaturated ester group are positioned at the opposite sides of the carbon-carbon double bond can not carry out intramolecular pyridine cyclization reaction but intermolecular polymerization reaction, so that the product yield and the purity are reduced.
Claims (12)
1. A method for preparing 2,3-dichloro-5-trifluoromethylpyridine, comprising the steps of:
(1) Condensing 1, 1-trifluoroacetone and nitromethane in a solvent A under the action of alkali A, and then acidifying to obtain a compound shown in a formula II;
Ⅱ
the alkali A is one or a combination of sodium hydroxide, potassium hydroxide and lithium hydroxide;
the solvent A is one or a combination of water, C1-C4 low-carbon alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether or toluene;
(2) Condensing a compound shown in a formula II and oxalic acid diester in a solvent B under the action of alkali B to obtain a reaction solution containing a compound shown in a formula III, directly carrying out reduction-cyclization reaction on the compound shown in the formula III in the presence of a catalyst without separation, and then acidifying to obtain a compound shown in a formula IV;
Ⅲ Ⅳ
wherein the compound of formula III isIn the formula, R is methyl, ethyl, propyl, isopropyl, tertiary butyl or other C 4 H 9 Butyl, M is K, na or Li;
the alkali B is sodium hydroxide solid, potassium hydroxide solid, lithium hydroxide solid, sodium methoxide solid, sodium ethoxide solid, sodium tert-butoxide solid, sodium methoxide methanol solution or sodium ethoxide ethanol solution;
the solvent B is one or a combination of C1-C4 low-carbon alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether or toluene;
the catalyst consists of a main catalyst and an auxiliary catalyst, wherein the main catalyst is a palladium-carbon catalyst or a Raney nickel catalyst, and the auxiliary catalyst is triethylamine, tri-n-butylamine, pyridine, 4-dimethylaminopyridine, triphenylphosphine or diphenyl sulfide;
(3) In a solvent C, carrying out chlorination reaction on a compound shown in the formula IV and a chlorinated reagent to obtain 2,3-dichloro-5-trifluoromethylpyridine (I);
Ⅰ
the solvent C is one or the combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane or chlorobenzene; the chlorinated reagent is one or the combination of more than two of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, diphosgene or triphosgene.
2. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein the reaction in step (1) comprises one or more of the following conditions:
a. the mass ratio of the solvent A to the 1, 1-trifluoroacetone is (2-10) to 1;
b. the molar ratio of the alkali A to the 1, 1-trifluoroacetone is (1.0-1.5): 1;
c. the molar ratio of the nitromethane to the 1, 1-trifluoroacetone is (1.0-1.5) to 1;
d. the condensation reaction temperature is-40-40 ℃;
e. the condensation reaction time is 0.5-5 hours;
f. hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid is used for acidification, and the molar ratio of the acid to 1, 1-trifluoroacetone is (0.4-1.5): 1.
3. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein in step (1), the base A is added as a solution prepared as the solvent A.
4. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein, in the step (1), the condensation reaction temperature is-10 to 10 ℃; the condensation reaction time is 2-3 hours.
5. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein the condensation reaction in step (2) comprises one or more of the following conditions:
i. the mass ratio of the solvent B to the compound shown in the formula II is (1-15): 1;
the molar ratio of the base B to the compound of formula II is (1.0-1.5): 1;
the molar ratio of the oxalic acid diester to the compound of formula II is (1.0-1.5): 1;
the condensation reaction temperature is 10-80 ℃;
v. the condensation reaction time is 1-5 hours.
6. The process for producing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein the condensation reaction in the step (2) is carried out at a temperature of 20 to 40 ℃ for 2 to 3 hours.
7. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein in the solvent A of step (1) and the solvent B of step (2), the C1-C4 lower alcohol is one or a combination of methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol.
8. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein the reduction-cyclization reaction in step (2) comprises one or more of the following conditions:
A. the mass of the palladium-carbon catalyst is 0.5-10% of that of the compound shown in the formula II;
B. the mass of the Raney nickel catalyst is 5-25% of that of the compound shown in the formula II;
C. the mass of the cocatalyst is 0.1-0.5% of that of the compound of the formula II;
D. the reduction-cyclization reaction temperature is 20 to 100 ℃, and the hydrogen pressure is 0.1 to 0.5MPa;
E. the reduction-cyclization reaction time is 3 to 10 hours.
9. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein the reduction-cyclization reaction in step (2) comprises one or more of the following conditions:
A. the mass of the palladium-carbon catalyst is 1-5% of that of the compound shown in the formula II;
B. the mass of the Raney nickel catalyst is 10-15% of that of the compound shown in the formula II;
C. the mass of the cocatalyst is 0.3-0.4% of that of the compound of the formula II;
D. the reduction-cyclization reaction temperature is 30 to 60 ℃, and the hydrogen pressure is 0.2 to 0.4MPa;
E. the reduction-cyclization reaction time is 4-8 hours.
10. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein in the step (2), hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid is used for the acidification, and the molar ratio of the acid to the compound of formula II is (0.4-1.5): 1.
11. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein the reaction in the step (3) comprises one or more of the following conditions:
the mass ratio of the solvent C to the compound shown in the formula IV is (0-10) to 1;
the molar ratio of the chlorinated reagent to the compound shown in the formula IV is (0.5-10) to 1;
III, the temperature of the chlorination reaction is 50-110 ℃;
IV, the chlorination reaction time is 2-18 hours.
12. The process for preparing 2,3-dichloro-5-trifluoromethylpyridine according to claim 1, wherein in the step (3), the molar ratio of the chlorinating reagent to the compound of formula IV is (1.0-5.0): 1; the chlorination reaction temperature is 60-80 ℃; the chlorination reaction time is 4-8 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062914A (en) * | 2006-04-28 | 2007-10-31 | 山东广恒化工有限公司 | Preparation method of 2-chlorin-3-trifluoro picoline |
| JP2012193124A (en) * | 2011-03-15 | 2012-10-11 | Sumitomo Chemical Co Ltd | Method for producing 2,3-dichloropyridine |
| CN103288718A (en) * | 2013-06-26 | 2013-09-11 | 联化科技股份有限公司 | Preparation method of 2-chloro-5-tirfluoromethylpyridine |
| CN104557683A (en) * | 2013-10-09 | 2015-04-29 | 郁建涵 | Preparation method of 2,3-dichloro-5-trifluoromethylpyridine |
| CN110818622A (en) * | 2018-08-08 | 2020-02-21 | 新发药业有限公司 | Preparation method of 2, 3-dichloropyridine |
Family Cites Families (1)
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| KR102366955B1 (en) * | 2017-12-06 | 2022-02-23 | 제지앙 란티안 엔바이론멘탈 프로텍션 하이테크 코포레이션 리미티드 | Method for the preparation of 2,3-dichloro-5-trifluoromethylpyridine |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062914A (en) * | 2006-04-28 | 2007-10-31 | 山东广恒化工有限公司 | Preparation method of 2-chlorin-3-trifluoro picoline |
| JP2012193124A (en) * | 2011-03-15 | 2012-10-11 | Sumitomo Chemical Co Ltd | Method for producing 2,3-dichloropyridine |
| CN103288718A (en) * | 2013-06-26 | 2013-09-11 | 联化科技股份有限公司 | Preparation method of 2-chloro-5-tirfluoromethylpyridine |
| CN104557683A (en) * | 2013-10-09 | 2015-04-29 | 郁建涵 | Preparation method of 2,3-dichloro-5-trifluoromethylpyridine |
| CN110818622A (en) * | 2018-08-08 | 2020-02-21 | 新发药业有限公司 | Preparation method of 2, 3-dichloropyridine |
Non-Patent Citations (2)
| Title |
|---|
| Preparation of 2,3-dichloro-5-trichloro(fluoro)methyl pyridines;Du, Hanquan等;《有机氟工业》;20101231;第1卷;15-18 * |
| Some new 2-substituted 5-trifluoromethylpyridines;Haga, Takahiro等;《Heterocycles 》;19841231;第22卷(第1期);117-24 * |
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