CN108794320B - Preparation method of 2,4, 5-trifluorophenylacetic acid - Google Patents
Preparation method of 2,4, 5-trifluorophenylacetic acid Download PDFInfo
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- CN108794320B CN108794320B CN201710291920.7A CN201710291920A CN108794320B CN 108794320 B CN108794320 B CN 108794320B CN 201710291920 A CN201710291920 A CN 201710291920A CN 108794320 B CN108794320 B CN 108794320B
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- YSQLGGQUQDTBSL-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(F)C=C1F YSQLGGQUQDTBSL-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000005859 coupling reaction Methods 0.000 claims abstract description 22
- XFGUFAPXHXFYKH-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetaldehyde Chemical compound FC1=CC(F)=C(CC=O)C=C1F XFGUFAPXHXFYKH-UHFFFAOYSA-N 0.000 claims abstract description 17
- LEEYFGDQDBEGPR-UHFFFAOYSA-N 2,4,5-trifluorobenzenediazonium Chemical class FC1=CC(F)=C([N+]#N)C=C1F LEEYFGDQDBEGPR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005977 Ethylene Substances 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000003054 catalyst Substances 0.000 claims description 25
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 14
- 239000002184 metal Substances 0.000 claims description 14
- 230000008878 coupling Effects 0.000 claims description 13
- 238000010168 coupling process Methods 0.000 claims description 13
- 239000003444 phase transfer catalyst Substances 0.000 claims description 13
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 12
- 239000012954 diazonium Substances 0.000 claims description 12
- 150000001989 diazonium salts Chemical class 0.000 claims description 12
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 12
- 235000010288 sodium nitrite Nutrition 0.000 claims description 12
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 claims description 10
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 10
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 10
- QMYVWJVVVMIBMM-UHFFFAOYSA-N 2,4,5-trifluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1F QMYVWJVVVMIBMM-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 8
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 8
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 8
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 8
- 229940045803 cuprous chloride Drugs 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 8
- 229960002218 sodium chlorite Drugs 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 5
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 5
- ZMMDPCMYTCRWFF-UHFFFAOYSA-J dicopper;carbonate;dihydroxide Chemical compound [OH-].[OH-].[Cu+2].[Cu+2].[O-]C([O-])=O ZMMDPCMYTCRWFF-UHFFFAOYSA-J 0.000 claims description 5
- -1 gem-dichloroethylene Chemical compound 0.000 claims description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 5
- ODTSDWCGLRVBHJ-UHFFFAOYSA-M tetrahexylazanium;chloride Chemical compound [Cl-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC ODTSDWCGLRVBHJ-UHFFFAOYSA-M 0.000 claims description 5
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 claims description 5
- SNNIPOQLGBPXPS-UHFFFAOYSA-M tetraoctylazanium;chloride Chemical compound [Cl-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC SNNIPOQLGBPXPS-UHFFFAOYSA-M 0.000 claims description 5
- JRLISGAUAJZAGL-UHFFFAOYSA-M tridodecyl(methyl)azanium;iodide Chemical compound [I-].CCCCCCCCCCCC[N+](C)(CCCCCCCCCCCC)CCCCCCCCCCCC JRLISGAUAJZAGL-UHFFFAOYSA-M 0.000 claims description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
- OYUNTGBISCIYPW-UHFFFAOYSA-N 2-chloroprop-2-enenitrile Chemical compound ClC(=C)C#N OYUNTGBISCIYPW-UHFFFAOYSA-N 0.000 claims description 4
- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- 229940116318 copper carbonate Drugs 0.000 claims description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 4
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 4
- 229960003280 cupric chloride Drugs 0.000 claims description 4
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 4
- 229940112669 cuprous oxide Drugs 0.000 claims description 4
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 4
- 239000011790 ferrous sulphate Substances 0.000 claims description 4
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 4
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 4
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 claims description 4
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 3
- FJTRNRFAIZEJJJ-UHFFFAOYSA-N 1,1-dimethoxyethene Chemical group COC(=C)OC FJTRNRFAIZEJJJ-UHFFFAOYSA-N 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000001931 aliphatic group Chemical group 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HCVIQIZKZQAPPH-UHFFFAOYSA-N [1-chloro-2-(2,4,5-trifluorophenyl)ethyl] acetate Chemical compound C(C)(=O)OC(CC1=C(C=C(C(=C1)F)F)F)Cl HCVIQIZKZQAPPH-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 150000008378 aryl ethers Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000002560 nitrile group Chemical group 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 2
- YIRQTJXLMOIZAJ-UHFFFAOYSA-N 2,2-dichloro-3-(2,4,5-trifluorophenyl)propanenitrile Chemical compound ClC(C#N)(CC1=C(C=C(C(=C1)F)F)F)Cl YIRQTJXLMOIZAJ-UHFFFAOYSA-N 0.000 description 2
- CZRLFTWJNYKAQR-UHFFFAOYSA-N C(C)=O.FC1=CC=C(C(=C1)F)F Chemical compound C(C)=O.FC1=CC=C(C(=C1)F)F CZRLFTWJNYKAQR-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- SFHWZYWTZNRADI-UHFFFAOYSA-N methyl 2-chloro-3-(2,4,5-trifluorophenyl)propanoate Chemical compound COC(=O)C(Cl)CC1=CC(F)=C(F)C=C1F SFHWZYWTZNRADI-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- FTPSNPSLDDXRTB-UHFFFAOYSA-N 1-(1-chloroethoxy)-2,4,5-trifluorobenzene Chemical compound ClC(C)OC1=C(C=C(C(=C1)F)F)F FTPSNPSLDDXRTB-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- RJYMRRJVDRJMJW-UHFFFAOYSA-L dibromomanganese Chemical compound Br[Mn]Br RJYMRRJVDRJMJW-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 2,4, 5-trifluorophenylacetic acid. The method comprises the following steps: (1) carrying out coupling reaction on 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A and substituted ethylene with a structure shown as a formula II to obtain an intermediate; and (2) hydrolyzing or oxidizing the intermediate to obtain 2,4, 5-trifluorophenylacetic acid with a structure shown in a formula I; the intermediate comprises a compound with a structure shown in a formula IV or 2,4, 5-trifluoro-phenylacetaldehyde with a structure shown in a formula C.
Description
Technical Field
The invention relates to intermediate preparation, in particular to a preparation method of 2,4, 5-trifluoro phenylacetic acid.
Background
2,4, 5-trifluoro-phenylacetic acid is an important intermediate for synthesizing a new medicine Sitagliptin for treating diabetes. The preparation method in the prior art is reported as follows:
US2004068141 reports that 2,4, 5-trifluorobromobenzene and diethyl malonate are used as raw materials to obtain 2,4, 5-trifluorophenylacetic acid through coupling reaction and hydrolysis deacidification reaction, and the method is harsh in reaction conditions and high in industrial production cost.
U.S. patent US20040077901 reports that 2,4, 5-trifluorobromobenzene undergoes Grignard reaction and substitution reaction with allyl bromide to obtain 1- (2-allyl) -2,4, 5-trifluorobenzene, and finally the 1- (2-allyl) -2,4, 5-trifluorobenzene is oxidized by ruthenium trichloride and sodium periodate to obtain 2,4, 5-trifluorophenylacetic acid, and the oxidizing agent in the route is high in price and is not suitable for industrial production.
Chinese patent CN1749232 reports that 1,2, 4-trifluorobenzene is used as raw material, and 2,4, 5-trifluorobenzene acetic acid is obtained through chloromethylation, cyanation and hydrolysis, and the route uses highly toxic cyanide, so that certain potential safety hazard is generated in production.
Therefore, there is an urgent need in the art to provide a method for preparing 2,4, 5-trifluorophenylacetic acid, which has the advantages of simple process flow, mild reaction conditions, simple and convenient post-treatment, high product purity and low cost.
Disclosure of Invention
The invention aims to provide a novel preparation method of 2,4, 5-trifluoro-phenylacetic acid.
The invention provides a preparation method of a compound 2,4, 5-trifluoro-phenylacetic acid with a structure shown in a formula I, which comprises the following steps:
(1) carrying out coupling reaction on 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A and substituted ethylene with a structure shown as a formula II to obtain an intermediate; and
(2) hydrolyzing or oxidizing the intermediate to obtain 2,4, 5-trifluorophenylacetic acid with a structure shown in a formula I;
the intermediate comprises a compound with a structure shown in a formula IV or 2,4, 5-trifluoro-phenylacetaldehyde with a structure shown in a formula C;
wherein R is1Substituents selected from aliphatic or aromatic structures containing 1 to 20 carbon atomsChlorine, bromine, iodine, nitro, nitrile group, and ester group; r2Selected from hydrogen, chlorine, bromine, iodine, nitro, nitrile, aliphatic or aromatic ether groups.
In another preferred embodiment, the solvent used in the method is selected from one or two or more of the following: tetrahydrofuran, acetonitrile, acetone, methanol, ethanol, and dimethyl sulfoxide; acetone is more preferred.
In another preferred embodiment, R1Is a substituent of an aliphatic or aromatic structure containing 1 to 20 carbon atoms; r2Is hydrogen; the compound with the structure shown in the formula II is preferably vinyl methyl ether, vinyl ethyl ether, vinyl butyl ether, vinyl acetate or methyl acrylate.
In another preferred embodiment, R1And R2Are respectively selected from aliphatic or aromatic ether group containing 1 to 20 carbon atoms, chlorine, bromine, iodine, nitro, nitrile group or aliphatic group; the compound with the structure shown in the formula II is preferably selected from dichloroethylene, 2-chloroacrylonitrile or 1, 1-dimethoxyethylene.
In one embodiment of the invention, the method comprises the steps of:
(1) salifying 2,4, 5-trifluoroaniline with a structure shown as a formula III and hydrochloric acid, and adding sodium nitrite to obtain 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A;
(2) carrying out coupling reaction on 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A and substituted ethylene with a structure shown as a formula II to obtain an intermediate with a structure shown as a formula IV;
(3) hydrolyzing the intermediate with the structure shown in the formula IV to obtain 2,4, 5-trifluoro-phenylacetaldehyde with the structure shown in the formula C; and
(4) oxidizing 2,4, 5-trifluoro-phenylacetaldehyde with a structure shown in a formula C to obtain 2,4, 5-trifluoro-phenylacetic acid with a structure shown in a formula I;
in another preferred example, the oxidant in step (4) is selected from sodium chlorite, sodium hypochlorite, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, or sodium persulfate; more preferably from sodium chlorite or m-chloroperoxybenzoic acid.
In another preferred embodiment, the reaction temperature for the diazonium salt preparation in step (1) is from-10 ℃ to 5 ℃, more preferably from-5 ℃ to 0 ℃; the reaction temperature of the coupling in the step (2) is-10-5 ℃, and more preferably-5-0 ℃; the reaction temperature in the step (3) is 0-60 ℃, and more preferably 25-30 ℃; the reaction temperature in step (4) is-10 ℃ to 30 ℃, more preferably 0 ℃ to 5 ℃.
In another embodiment of the present invention, the method comprises the steps of:
(1) salifying 2,4, 5-trifluoroaniline with a structure shown as a formula III and hydrochloric acid, and adding sodium nitrite to obtain 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A;
(2) carrying out coupling reaction on 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A and substituted ethylene with a structure shown as a formula II to obtain an intermediate with a structure shown as a formula IV; and
(3) hydrolyzing the intermediate shown in the structural formula IV to obtain the 2,4, 5-trifluorophenylacetic acid shown in the structural formula I.
In another preferred example, the hydrolysis catalyst in step (3) is 30% sulfuric acid, concentrated hydrochloric acid, 30% aqueous sodium hydroxide solution, or 30% aqueous potassium hydroxide solution.
In another preferred embodiment, the reaction temperature for the diazonium salt preparation in step (1) is from-10 ℃ to 5 ℃, more preferably from-5 ℃ to 0 ℃; the reaction temperature of the coupling in the step (2) is-10-5 ℃, and more preferably-5-0 ℃; the reaction temperature in step (3) is 0 to 60 ℃ and more preferably 25 to 30 ℃.
The coupling catalyst used in step (2) of the above preparation method provided by the present invention is selected from a metal catalyst, a phase transfer catalyst, or a combination thereof; preferably a combination of a metal catalyst and a phase transfer catalyst; the metal catalyst is selected from one or more of the following combinations: ferrocene, ferric acetylacetonate, ferrous sulfate, copper powder, cupric chloride, cuprous chloride, cupric sulfate, basic cupric carbonate, cuprous iodide, cupric nitrate, cupric hydroxide, and cuprous oxide; preferably one or a combination of two or more of the following: ferrocene, cuprous chloride, and basic copper carbonate; the phase transfer catalyst is selected from one or more of the following combinations: tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and tridodecylmethylammonium iodide; preferably methyl trioctyl ammonium chloride, and/or tetrabutylammonium bromide.
Accordingly, the invention provides the preparation method of the 2,4, 5-trifluorophenylacetic acid, which has the advantages of simple process flow, mild reaction conditions, simple and convenient post-treatment, high product purity and low cost.
Detailed Description
The inventors of the present invention have conducted extensive and intensive studies and found that a 2,4, 5-trifluorobenzene diazonium salt obtained from 2,4, 5-trifluoroaniline as a raw material can be obtained by subjecting a substituted ethylene to a coupling reaction to obtain an intermediate product, and subjecting the intermediate product to hydrolysis or oxidation to obtain 2,4, 5-trifluorophenylacetic acid.
The invention relates to a main compound or a general formula of the compound as shown in the table I:
wherein when R is2When it is hydrogen, R1A substituent selected from aliphatic or aromatic structures containing 1 to 20 carbon atoms; preferably selected from vinyl methyl ether, vinyl ethyl ether, vinyl butyl ether, or vinyl acetate;
when R is2Selected from chlorine, bromine, iodine, nitro, nitrile, aliphatic or aromatic ether groups, R1Or from the group consisting of chlorine, bromine, iodine, nitro, nitrile, aliphatic or aromatic ether radicals, R1And R2May be the same or different.
In one embodiment of the present invention, R in the main compound or general formula (I) according to the invention1And R2Can be changed by correspondingly different waysThe 2,4, 5-trifluoro-phenylacetic acid is obtained by the line preparation.
When monosubstituted ethylene is used as a coupling substrate, the route can be as follows:
specifically, in the first step, 2,4, 5-trifluoroaniline and hydrochloric acid are mixed, and then sodium nitrite is added to obtain intermediate 2,4, 5-trifluorobenzene diazonium salt with the structure shown in the formula A;
secondly, performing coupling reaction on the obtained 2,4, 5-trifluorobenzene diazonium salt and monosubstituted ethylene to obtain an intermediate state shown in a structural formula B;
thirdly, mixing acid or alkali, a catalyst and the intermediate substance shown in the structural formula B to obtain 2,4, 5-trifluoro-phenylacetaldehyde shown in the structural formula C;
and fourthly, mixing the 2,4, 5-trifluorophenylacetaldehyde shown in the structural formula C with a premix to obtain the 2,4, 5-trifluorophenylacetic acid shown in the structural formula I.
In the first step, the concentration of the hydrochloric acid is 20-30 v/v%; the sodium nitrite is 35-45 w/v% sodium nitrite water solution; the reaction temperature is-10 ℃ to 5 ℃, preferably-5 ℃ to 0 ℃, and more preferably 0 ℃.
In the second step, the mono-substituted ethylene is a compound shown as a structure II, wherein R is2Is hydrogen, R1A substituent selected from aliphatic or aromatic structures containing 1 to 20 carbon atoms; preferably selected from vinyl methyl ether, vinyl ethyl ether, vinyl butyl ether, vinyl acetate, or methyl acrylate.
The coupling catalyst used in the second step above is selected from a metal catalyst, a phase transfer catalyst, or a combination thereof; a combination of metal catalysts and phase transfer catalysts is preferred. The metal catalyst is selected from one or more of the following combinations: ferrocene, ferric acetylacetonate, ferrous sulfate, copper powder, cupric chloride, cuprous chloride, cupric sulfate, basic cupric carbonate, cuprous iodide, cupric nitrate, cupric hydroxide, and cuprous oxide; preferably one or a combination of two or more of the following: ferrocene, cuprous chloride, and basic copper carbonate; the phase transfer catalyst is selected from one or more of the following combinations: tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and tridodecylmethylammonium iodide; preferably methyl trioctyl ammonium chloride, and/or tetrabutylammonium bromide.
The temperature in the second step is-10 deg.C-5 deg.C, preferably-5 deg.C-0 deg.C, and more preferably 0 deg.C.
In one embodiment of the present invention, the second step is to mix the mono-substituted ethylene, the coupling catalyst and the reaction solvent, and then to drop the diazonium salt system obtained in the first step at the temperature, wherein the dropping speed is slow, and the temperature is kept for 5 to 10 hours after the dropping.
In the third step, the acid is 25-35 v/v% hydrochloric acid, and the base is lithium hydroxide; the catalyst is selected from one or more of the following combinations: tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and tridodecylmethylammonium iodide; preferably methyl trioctyl ammonium chloride, and/or tetrabutylammonium bromide.
The temperature in the third step is 0 to 60 ℃, preferably 25 to 30 ℃.
In one embodiment of the present invention, the third step is to mix an acid or a base, water, an organic solvent and a catalyst, and then add the mixture dropwise to the intermediate state of formula B obtained in the second step, and keep the temperature for 20 to 30 hours to obtain 2,4, 5-trifluorophenylacetaldehyde.
The oxidizing agent used in the fourth step is selected from sodium chlorite, sodium hypochlorite, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, or sodium persulfate, and sodium chlorite is preferred.
In an embodiment of the present invention, in the fourth step, an oxidizing agent is dropped into 2,4, 5-trifluorophenylacetaldehyde, after the reaction is performed at-10 ℃ to 30 ℃ (preferably 0 ℃ to 5 ℃), pH is adjusted to be higher than 10, the oxidizing agent is quenched and then layered, after the pH of the aqueous phase is lower than 3, extraction is performed, and the organic phase is concentrated, rectified, filtered and dried to obtain 2,4, 5-trifluorophenylacetic acid with a structure shown in formula i.
The organic solvent used in each step is tetrahydrofuran, acetonitrile, acetone, methanol, ethanol, dimethyl sulfoxide or a mixture thereof; acetone is preferred.
When geminally disubstituted ethylene is used as a coupling substrate, the route can be as follows:
specifically, in the first step, 2,4, 5-trifluoroaniline and hydrochloric acid are mixed, and then sodium nitrite is added to obtain intermediate 2,4, 5-trifluorobenzene diazonium salt with the structure shown in the formula A;
secondly, performing coupling reaction on the obtained 2,4, 5-trifluorobenzene diazonium salt and geminal disubstituted ethylene to obtain an intermediate shown in a structural formula IV;
and thirdly, hydrolyzing the intermediate shown in the structural formula IV into 2,4, 5-trifluorophenylacetic acid shown in the structural formula I under the action of strong acid or strong alkali.
In the first step, the concentration of the hydrochloric acid is 20-30 v/v%; the sodium nitrite is 35-45 w/v% sodium nitrite water solution; the reaction temperature is-10 ℃ to 5 ℃, preferably-5 ℃ to 0 ℃, and more preferably 0 ℃.
In the second step, the geminally disubstituted ethylene is a compound with a structure shown as II, wherein R is1And R2Respectively selected from chlorine, bromine, iodine, nitryl, nitrile group, aliphatic or aromatic ether group and aliphatic group; the geminally disubstituted ethylene is preferably 2-chloroacrylonitrile.
The coupling catalyst used in the second step above is selected from a metal catalyst, a phase transfer catalyst, or a combination thereof; a combination of metal catalysts and phase transfer catalysts is preferred. The metal catalyst is a metal from VIB to IB (left to right) in the periodic table of elements and derivatives thereof, such as copper powder, cupric chloride, cuprous bromide, cupric sulfate, basic cupric carbonate, cuprous iodide, cupric nitrate, cupric hydroxide, cuprous oxide, ferrocene, ferric acetylacetonate, ferrous sulfate, ferric chloride, ferrous chloride, cobaltous bromide, manganese dichloride, manganese dibromide or mixtures thereof; wherein cuprous chloride and ferrocene are preferred; the phase transfer catalyst is tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, tridodecylmethylammonium iodide or a mixture thereof.
The temperature in the second step is-10 deg.C-5 deg.C, preferably-5 deg.C-0 deg.C, and more preferably 0 deg.C.
In one embodiment of the present invention, the geminal disubstituted ethylene, the coupling catalyst and the reaction solvent are mixed in the second step, and then the diazonium salt system obtained in the first step is dropwise added at the temperature, wherein the dropwise adding speed is slow, and the temperature is kept for 5 to 10 hours after the dropwise adding.
In the third step, the strong acid is 30% sulfuric acid, concentrated hydrochloric acid and the like; the strong base is 30% sodium hydroxide aqueous solution, 30% potassium hydroxide aqueous solution, etc.
The reaction temperature of the third hydrolysis step is 0 to 60 ℃, preferably 25 to 30 ℃.
The organic solvent used in each step is tetrahydrofuran, acetonitrile, acetone, methanol, ethanol, dimethyl sulfoxide or a mixture thereof; acetone is preferred.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The main advantages of the invention are:
the preparation method provided by the invention has the advantages of simple process flow, mild reaction conditions, simple and convenient post-treatment, high product purity and low cost.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified. The weight volume percentage units in the present invention are well known to those skilled in the art and refer to, for example, the weight of solute in a 100 ml solution. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Preparation of 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate
147g (1mol) of 2,4, 5-trifluoroaniline and 694g (4.56mol) of 24% hydrochloric acid are added into a 2L four-mouth bottle, the mixture is heated and stirred, the system is stirred for 1 hour after being dissolved clearly, the temperature is reduced to 0 ℃, 40% aqueous solution containing sodium nitrite (82.8g) is dripped, the temperature is kept for 1 to 2 hours after the dripping is finished, and the diazonium salt is completely prepared. In another 2L four-necked flask, 129g (1.5mol) of vinyl acetate, 18.57g (0.1mol) of ferrocene and 200g (2w/w) of acetone are mixed, the temperature is reduced to 0 ℃, a diazonium salt system is slowly dripped for 2 to 3 hours, the temperature is kept for 6 to 8 hours after dripping, filtration is carried out, and the organic phase is recrystallized by 50g of ethyl acetate and 200g of n-heptane to obtain the crude product of 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate with the yield of 60 percent.
1H NMR(400MHz,CDCl3):δ7.18-7.00(m,1H),7.00-6.83(m,1H),6.62-6.47(m,1H),3.42-3.15(d,2H),2.10(s,3H).
Example 2
Preparation of methyl 2-chloro-3- (2,4, 5-trifluorophenyl) -propionate
The reaction was terminated in the same manner as in example 1 except that 129.2g of methyl acrylate was used instead of vinyl acetate, to give a crude product of methyl 2-chloro-3- (2,4, 5-trifluorophenyl) -propionate in a yield of 59%.
1H NMR(400MHz,CDCl3):δ7.17-7.00(m,1H),7.00-6.81(m,1H),4.54-4.41(m,1H),3.79(s,3H),3.45-3.07(m,2H).
Example 3
Preparation of 2, 2-dichloro-3- (2,4, 5-trifluorophenyl) -propionitrile
The reaction was terminated in the same manner as in example 1 except that 131.3g of 2-chloroacrylonitrile was used instead of vinyl acetate, to give a crude product of 2, 2-dichloro-3- (2,4, 5-trifluorophenyl) -propionitrile in a yield of 57%.
1H NMR(400MHz,CDCl3):δ7.41-7.18(m,1H),7.18-6.91(m,1H),3.78(s,2H).
Example 4
Preparation of 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate
147g (1mol) of 2,4, 5-trifluoroaniline and 694g (4.56mol) of 24% hydrochloric acid are added into a 2L four-mouth bottle, the mixture is heated and stirred, the system is stirred for 1 hour after being dissolved clearly, the temperature is reduced to 0 ℃, 40% aqueous solution containing sodium nitrite (82.8g) is dripped, the temperature is kept for 1 to 2 hours after the dripping is finished, and the diazonium salt is completely prepared. In another 2L four-necked flask, 129g (1.5mol) of vinyl acetate, 11.95g (0.054mol) of basic copper carbonate, 12g (0.03mol) of trioctylmethylammonium chloride, 42.76g (1mol) of sodium bicarbonate and 200g (2w/w) of acetone are mixed, the temperature is reduced to 0 ℃, a diazonium salt system is slowly dripped for 2-3 hours, the temperature is kept for 6-8 hours after the dripping is finished, the mixture is filtered, and the organic phase is recrystallized by 50g of ethyl acetate and 200g of n-heptane to obtain the crude product of the 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate, wherein the yield is 70%.
1H NMR(400MHz,CDCl3):δ7.18-7.00(m,1H),7.00-6.83(m,1H),6.62-6.47(m,1H),3.42-3.15(d,2H),2.10(s,3H).
Example 5
Preparation of 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate
The reaction was terminated in the same manner as in example 4 except for using 5.38g of cuprous chloride in place of basic cupric carbonate to give a crude product of ethyl 1-chloro-2- (2,4, 5-trifluorophenyl) -acetate in a yield of 70%.
1H NMR(400MHz,CDCl3):δ7.18-7.00(m,1H),7.00-6.83(m,1H),6.62-6.47(m,1H),3.42-3.15(d,2H),2.10(s,3H).
Example 6
Preparation of 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate
The reaction was terminated in the same manner as in example 4 except for using 10g of tetrabutylammonium bromide in place of the trioctylmethylammonium chloride, to give a crude product of 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate in a yield of 69%.
1H NMR(400MHz,CDCl3):δ7.18-7.00(m,1H),7.00-6.83(m,1H),6.62-6.47(m,1H),3.42-3.15(d,2H),2.10(s,3H).
Example 7
Preparation of 2,4, 5-trifluorophenylacetaldehyde
In a 2L four-necked flask, 132g (1.08mol) of 30% hydrochloric acid, 132g of water, 160g of acetone and 3.66g (8.14mmol) of trioctylmethylammonium chloride are mixed, stirred at 25-30 ℃, 98g (0.27mol) of crude 1-chloro-2- (2,4, 5-trifluorophenyl) -ethyl acetate is added dropwise, the mixture is subjected to heat preservation reaction for 24 hours to obtain a 2,4, 5-trifluorophenylacetaldehyde solution, the external standard yield is 85%, and the solution is directly put into the next step.
Example 8
Preparation of 2,4, 5-trifluorophenylacetaldehyde
The reaction was completed in the same manner as in example 7 except that 26g of lithium hydroxide was used instead of 30% hydrochloric acid to give a 2,4, 5-trifluorophenylacetaldehyde solution in an external standard yield of 76%, which was directly used in the next step.
Example 9
Preparation of 2,4, 5-trifluorophenylacetic acid
Cooling the solution containing about 42g (0.22mol) of the crude product of 2,4, 5-trifluoro-phenylacetaldehyde to 0 ℃, dropwise adding 30 percent aqueous solution containing 40g (0.44mol) of sodium chlorite, completing dropwise adding within 2 hours, and reacting for 4 hours at the temperature of 0-5 ℃. Adding NaOH solid at low temperature to enable the pH value of the system to be more than 10, adding a proper amount of sodium sulfite solid to quench excessive oxidant, adding toluene, layering, adding 30% hydrochloric acid into a water phase to enable the pH value to be less than 3, adding toluene for extraction, concentrating organic phase under reduced pressure until no fraction is obtained, rectifying the residue in a kettle, collecting fractions, pulping the fractions by DCM, filtering to obtain a filter cake, and drying to obtain 33g of 2,4, 5-trifluorophenylacetic acid with the content of 99% and the yield of 80%.
1H NMR(400MHz,CDCl3):δ7.20-7.02(m,1H),7.02-6.85(m,1H),3.67(s,2H).
Example 10
Preparation of 2,4, 5-trifluorophenylacetic acid
The reaction was completed in the same manner as in example 9 except that 76.7g of m-chloroperoxybenzoic acid was used in place of sodium chlorite to obtain a crude product of 2,4, 5-trifluorophenylacetic acid having a content of 99% and a yield of 78%.
1H NMR(400MHz,CDCl3):δ7.20-7.02(m,1H),7.02-6.85(m,1H),3.67(s,2H).
Example 11
Preparation of 2,4, 5-trifluorophenylacetaldehyde
147g (1mol) of 2,4, 5-trifluoroaniline and 694g (4.56mol) of 24% hydrochloric acid are added into a 2L four-mouth bottle, the mixture is heated and stirred, the system is stirred for 1 hour after being dissolved clearly, the temperature is reduced to 0 ℃, 40% aqueous solution containing sodium nitrite (82.8g) is dripped, the temperature is kept for 1 to 2 hours after the dripping is finished, and the diazonium salt is completely prepared. Mixing 108.2g (1.5mol) of vinyl ethyl ether, 18.57g (0.1mol) of ferrocene and 200g (2w/w) of acetone in another 2L four-mouth bottle, cooling to 0 ℃, slowly dropwise adding a diazonium salt system for 2-3 hours, preserving heat for 6-8 hours after dropwise adding is finished, gradually hydrolyzing 1- (2-chloro-2-ethoxy) -2,4, 5-trifluorobenzene generated in the system into 2,4, 5-trifluorobenzene acetaldehyde, prolonging the heat preservation time to ensure that the conversion is complete, extracting by methyl tert-butyl ether, and concentrating under reduced pressure to obtain a crude product of the 2,4, 5-trifluorobenzene acetaldehyde, wherein the external standard yield is 42%, and directly putting the crude product into the next step.
Example 12
Preparation of 2,4, 5-trifluorophenylacetic acid
Mixing 42g (0.22mol) of crude 2,4, 5-trifluorophenylacetaldehyde, 200g of tetrahydrofuran and 26.8g (0.22mol) of 30% hydrochloric acid in a 1L two-neck bottle, cooling to 0 ℃, dropwise adding 30% aqueous solution containing 40g (0.44mol) of sodium chlorite, finishing dripping after 2 hours, keeping the temperature at 0-5 ℃ for reaction for 4 hours, adding NaOH solid at low temperature to enable the pH of the system to be more than 10, adding a proper amount of sodium sulfite solid to quench excessive oxidant, adding toluene, layering, adding 30% hydrochloric acid in a water phase to enable the pH to be less than 3, adding toluene for extraction, concentrating organic phase under reduced pressure to be free of distillate, rectifying the residual kettle, collecting distillate, pulping the distillate with DCM, filtering to obtain a filter cake, and drying to obtain 33g of 2,4, 5-trifluorophenylacetic acid with the content of 99% and the yield.
1H NMR(400MHz,CDCl3):δ7.20-7.02(m,1H),7.02-6.85(m,1H),3.67(s,2H).
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (12)
1. A method for preparing 2,4, 5-trifluorophenylacetic acid, a compound represented by formula i, comprising the steps of:
(1) salifying 2,4, 5-trifluoroaniline with a structure shown as a formula III and hydrochloric acid, and adding sodium nitrite to obtain 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A;
(2) carrying out coupling reaction on 2,4, 5-trifluorobenzene diazonium salt with a structure shown as a formula A and substituted ethylene with a structure shown as a formula II to obtain an intermediate with a structure shown as a formula IV;
(3) hydrolyzing the intermediate with the structure shown in the formula IV to obtain 2,4, 5-trifluoro-phenylacetaldehyde with the structure shown in the formula C;
(4) oxidizing 2,4, 5-trifluoro-phenylacetaldehyde with a structure shown in a formula C to obtain 2,4, 5-trifluoro-phenylacetic acid with a structure shown in a formula I;
wherein the compound with the structure shown in the formula II is vinyl methyl ether, vinyl ethyl ether, vinyl butyl ether, vinyl acetate, methyl acrylate, gem-dichloroethylene, 2-chloropropene nitrile or 1, 1-dimethoxyethylene.
2. The method of claim 1, wherein the oxidizing agent in step (4) is selected from sodium chlorite, sodium hypochlorite, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid, or sodium persulfate.
3. The method of claim 1, wherein the diazonium salt is prepared at a reaction temperature of-10 ℃ to 5 ℃ in step (1) and the coupling at a reaction temperature of-10 ℃ to 5 ℃ in step (2); the reaction temperature in the step (3) is 0-60 ℃; the reaction temperature in the step (4) is-10 ℃ to 30 ℃.
4. The method of claim 1, wherein the diazonium salt is prepared at a reaction temperature of-5 ℃ to 0 ℃ in step (1).
5. The method of claim 1, wherein the reaction temperature for the coupling in step (2) is from-5 ℃ to 0 ℃.
6. The method according to claim 1, wherein the reaction temperature in the step (3) is 25 to 30 ℃.
7. The method according to claim 1, wherein the reaction temperature in the step (4) is 0 to 5 ℃.
8. The method according to claim 1, wherein the hydrolysis catalyst in the step (3) is 30% sulfuric acid, concentrated hydrochloric acid, a 30% aqueous solution of sodium hydroxide, or a 30% aqueous solution of potassium hydroxide.
9. The method of claim 1, wherein the coupling catalyst used in step (2) is selected from a metal catalyst, a phase transfer catalyst, or a combination thereof; the metal catalyst is selected from one or more of the following combinations: ferrocene, ferric acetylacetonate, ferrous sulfate, copper powder, cupric chloride, cuprous chloride, cupric sulfate, basic cupric carbonate, cuprous iodide, cupric nitrate, cupric hydroxide, and cuprous oxide; the phase transfer catalyst is selected from one or more of the following combinations: tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctylammonium chloride, methyltrioctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and tridodecylmethylammonium iodide.
10. The method of claim 9, wherein the coupling catalyst used in step (2) is a combination of a metal catalyst and a phase transfer catalyst.
11. The method according to claim 9, wherein the metal catalyst is one or a combination of two or more of the following: ferrocene, cuprous chloride, and basic copper carbonate.
12. The method of claim 9, wherein the phase transfer catalyst is methyltrioctylammonium chloride and/or tetrabutylammonium bromide.
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