CN108794320A - A kind of preparation method of 2,4,5- trifluoro benzene acetic acids - Google Patents
A kind of preparation method of 2,4,5- trifluoro benzene acetic acids Download PDFInfo
- Publication number
- CN108794320A CN108794320A CN201710291920.7A CN201710291920A CN108794320A CN 108794320 A CN108794320 A CN 108794320A CN 201710291920 A CN201710291920 A CN 201710291920A CN 108794320 A CN108794320 A CN 108794320A
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- CN
- China
- Prior art keywords
- formula
- preparation
- acid
- trifluoro
- ammonium
- Prior art date
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- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- CPHORTCGMDXMEI-UHFFFAOYSA-N C(C)(=O)O.FC1=CC=C(C(=C1)F)F Chemical class C(C)(=O)O.FC1=CC=C(C(=C1)F)F CPHORTCGMDXMEI-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000005859 coupling reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 claims abstract description 12
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000005977 Ethylene Substances 0.000 claims abstract description 9
- 229940100595 phenylacetaldehyde Drugs 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 32
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 22
- -1 chloroethenes Alkene Chemical class 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- 239000003863 metallic catalyst Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims description 11
- 235000010288 sodium nitrite Nutrition 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- CIZVQWNPBGYCGK-UHFFFAOYSA-N benzenediazonium Chemical class N#[N+]C1=CC=CC=C1 CIZVQWNPBGYCGK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 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
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 10
- OOMNPYBQJCAHFY-UHFFFAOYSA-N 2,4,5-tris(fluoromethyl)aniline Chemical class FCC1=C(N)C=C(C(=C1)CF)CF OOMNPYBQJCAHFY-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 235000011150 stannous chloride Nutrition 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 8
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical class FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 8
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 8
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229940116318 copper carbonate Drugs 0.000 claims description 8
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 8
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical group [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 8
- 229960002218 sodium chlorite Drugs 0.000 claims description 8
- 239000001119 stannous chloride Substances 0.000 claims description 8
- 229940117958 vinyl acetate Drugs 0.000 claims description 8
- 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 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 150000003839 salts Chemical class 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
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-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
- XKDUZXVNQOZCFC-UHFFFAOYSA-N hexan-1-amine;hydron;chloride Chemical class Cl.CCCCCCN XKDUZXVNQOZCFC-UHFFFAOYSA-N 0.000 claims description 5
- PHFDTSRDEZEOHG-UHFFFAOYSA-N hydron;octan-1-amine;chloride Chemical class Cl.CCCCCCCCN PHFDTSRDEZEOHG-UHFFFAOYSA-N 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 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
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 4
- AEJIMXVJZFYIHN-UHFFFAOYSA-N copper;dihydrate Chemical compound O.O.[Cu] AEJIMXVJZFYIHN-UHFFFAOYSA-N 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
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 4
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 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 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 claims description 3
- FJTRNRFAIZEJJJ-UHFFFAOYSA-N 1,1-dimethoxyethene Chemical group COC(=C)OC FJTRNRFAIZEJJJ-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 claims 1
- ZSAIDYISADJCTG-UHFFFAOYSA-N CC(CCCCCCC)P(CCCCCCCC)CCCCCCCC Chemical compound CC(CCCCCCC)P(CCCCCCCC)CCCCCCCC ZSAIDYISADJCTG-UHFFFAOYSA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- LEEYFGDQDBEGPR-UHFFFAOYSA-N 2,4,5-trifluorobenzenediazonium Chemical class FC1=CC(F)=C([N+]#N)C=C1F LEEYFGDQDBEGPR-UHFFFAOYSA-N 0.000 abstract description 3
- 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XFGUFAPXHXFYKH-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetaldehyde Chemical class FC1=CC(F)=C(CC=O)C=C1F XFGUFAPXHXFYKH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012954 diazonium Substances 0.000 description 5
- 150000001989 diazonium salts Chemical class 0.000 description 5
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 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
- 239000000243 solution Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical class FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-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
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 235000010344 sodium nitrate Nutrition 0.000 description 2
- 239000004317 sodium nitrate Substances 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
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-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
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 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
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical compound [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 description 1
- HDNHOKVFJHDYFT-UHFFFAOYSA-N [Cl].CC(CCCCCCC)P(CCCCCCCC)CCCCCCCC Chemical compound [Cl].CC(CCCCCCC)P(CCCCCCCC)CCCCCCCC HDNHOKVFJHDYFT-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- SCSHFLIEEIYUPB-UHFFFAOYSA-N acetic acid;1,2,3-trifluorobenzene Chemical compound CC(O)=O.FC1=CC=CC(F)=C1F SCSHFLIEEIYUPB-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 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
- UGWKCNDTYUOTQZ-UHFFFAOYSA-N copper;sulfuric acid Chemical compound [Cu].OS(O)(=O)=O UGWKCNDTYUOTQZ-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 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
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 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
- 239000002002 slurry Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing 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 kind of preparation methods of 2,4,5- trifluoro benzene acetic acids.The method includes the steps：(1) structure 2,4,5- trifluoro phenyl diazonium salt for example shown in formula A and the structure substituted ethylene as shown in formula II are subjected to coupling reaction, obtain intermediate；(2) intermediate is made to obtain structure 2,4,5- trifluoro benzene acetic acids as shown in formula I through hydrolyzing or aoxidizing；The intermediate includes structure such as IV compound represented of formula or structure the 2,4,5- trifluoros phenylacetaldehyde as shown in formula C.
Description
Technical field
The present invention relates to intermediate preparations, more particularly to a kind of preparation method of 2,4,5- trifluoro benzene acetic acids.
Background technology
2,4,5- trifluoro benzene acetic acids are a kind of important centres synthesizing the new drug Sitagliptin for treating diabetes
Body.There is following report to preparation method in the prior art：
United States Patent (USP) US2004068141 is reported with 2,4,5- trifluorobromobenzenes and diethyl malonate for raw material, by idol
2,4,5- trifluoro benzene acetic acids, the method severe reaction conditions, industrial production cost height is obtained by the reaction in connection reaction, hydrolysis depickling.
United States Patent (USP) US20040077901 reports 2,4,5- trifluorobromobenzenes and occurs by grignard reaction and allyl bromide, bromoallylene
Substitution reaction obtains 1- (2- allyls) -2, and 4,5- trifluoro-benzenes finally obtain 2,4 by ruthenium trichloride, sodium periodate oxidation,
5- trifluoro benzene acetic acids, the route oxidant price is high, is not suitable for industrialized production.
Chinese patent CN1749232 is reported with 1,2,4- trifluoro-benzene as raw material, by chloromethylation, cyanalation, hydrolysis
2,4,5- trifluoro benzene acetic acids are obtained, which has used hypertoxic cyanide, had some potential safety problems in production.
Therefore, there is an urgent need in the art to provide, a kind of technological process is simple, reaction condition is mild, post-processing is easy and product
Purity height, 2,4,5- trifluoro benzene acetic acid preparation methods at low cost.
Invention content
The present invention is intended to provide a kind of new 2,4,5- trifluoro benzene acetic acid preparation methods.
It is described the present invention provides a kind of preparation method of structure such as I compound represented of formula, 2,4,5- trifluoro benzene acetic acid
Method includes step：
(1) structure such as 2,4,5- trifluoros phenyl diazonium salt shown in formula A and the structure substituted ethylene as shown in formula II are carried out
Coupling reaction obtains intermediate；With
(2) intermediate is made to obtain structure 2,4,5- trifluoro benzene acetic acids as shown in formula I through hydrolyzing or aoxidizing；
The intermediate includes structure such as IV compound represented of formula or structure the 2,4,5- trifluoro-benzenes second as shown in formula C
Aldehyde；
Wherein, R1Substituent group, chlorine, bromine, iodine, nitro, nitrile selected from fat or aromatic structure containing 1 to 20 carbon atom
Base, aliphatic radical；R2Selected from hydrogen, chlorine, bromine, iodine, nitro, itrile group, aliphatic radical, fat or fragrant ether.
In another preferred example, the solvent used in the method is selected from following one or more：Tetrahydrofuran,
Acetonitrile, acetone, methanol, ethyl alcohol and dimethyl sulfoxide (DMSO)；More preferable acetone.
In another preferred example, R1For the substituent group of fat or aromatic structure containing 1 to 20 carbon atom；R2For hydrogen；It is described
Structure such as II compound represented preferred vinyl methyl ether of formula, vinyl ethyl ether, vinyl-n-butyl ether, vinylacetate or third
E pioic acid methyl ester.
In another preferred example, R1And R2Be respectively selected from containing the fatty or fragrant ether of 1 to 20 carbon atom, chlorine, bromine, iodine,
Nitro, itrile group or aliphatic radical；The structure such as II compound represented of formula is preferably together with dichloroethylene, 2- chloroacrylonitriles or 1,1- bis-
Methoxy-ethylene.
In one embodiment of the invention, the method includes the steps：
(1) after 2,4,5- trifluoromethyl anilines and hydrochloric acid are at salt as shown in formula III by structure, sodium nitrite is added, obtains structure
Such as 2,4,5- trifluoros phenyl diazonium salt shown in formula A；
(2) structure such as 2,4,5- trifluoros phenyl diazonium salt shown in formula A and the structure substituted ethylene as shown in formula II are carried out
Coupling reaction obtains structure intermediate as shown in formula IV；
(3) structure intermediate as shown in formula IV is made to obtain structure 2,4,5- trifluoros phenylacetaldehyde as shown in formula C through hydrolysis；
With
(4) structure 2,4,5- trifluoros phenylacetaldehyde as shown in formula C is oxidized obtains structure 2,4,5- trifluoros as shown in formula I
Phenylacetic acid；
In another preferred example, in step (4) oxidant be selected from sodium chlorite, sodium hypochlorite, hydrogen peroxide, Peracetic acid,
Metachloroperbenzoic acid or sodium peroxydisulfate；More preferably from sodium chlorite or metachloroperbenzoic acid.
In another preferred example, in step (1) diazol prepare reaction temperature be -10 DEG C -5 DEG C, more preferably -5 DEG C -
0℃；The reaction temperature being coupled in step (2) is -10 DEG C -5 DEG C, more preferably -5 DEG C -0 DEG C；Reaction temperature in step (3) is
0-60 DEG C, more preferably 25-30 DEG C；Reaction temperature in step (4) is -10 DEG C -30 DEG C, more preferably 0-5 DEG C.
In another embodiment of the invention, the method includes the steps：
(1) after 2,4,5- trifluoromethyl anilines and hydrochloric acid are at salt as shown in formula III by structure, sodium nitrite is added, obtains structure
Such as 2,4,5- trifluoros phenyl diazonium salt shown in formula A；
(2) structure such as 2,4,5- trifluoros phenyl diazonium salt shown in formula A and the structure substituted ethylene as shown in formula II are carried out
Coupling reaction obtains structure intermediate as shown in formula IV；With
(3) structure intermediate as shown in formula IV is made to obtain structure 2,4,5- trifluoro benzene acetic acids as shown in formula I through hydrolysis.
In another preferred example, hydrolyst is that 30% sulfuric acid, concentrated hydrochloric acid, 30% sodium hydroxide are water-soluble in step (3)
Liquid or 30% potassium hydroxide aqueous solution.
In another preferred example, in step (1) diazol prepare reaction temperature be -10 DEG C -5 DEG C, more preferably -5 DEG C -
0℃；The reaction temperature being coupled in step (2) is -10 DEG C -5 DEG C, more preferably -5 DEG C -0 DEG C；Reaction temperature in step (3) is
0-60 DEG C, more preferably 25-30 DEG C.
The coupling catalyst used in the step of above-mentioned preparation method provided by the invention (2) is selected from metallic catalyst, phase
Transfer catalyst, or combinations thereof；It is preferred that the combination of metallic catalyst and phase transfer catalyst；The metallic catalyst is selected from following
A combination of one or more：Ferrocene, ferric acetyl acetonade, ferrous sulfate, copper powder, copper chloride, stannous chloride, sulfuric acid
Copper, basic copper carbonate, cuprous iodide, copper nitrate, Kocide SD and cuprous oxide；It preferably is selected from following one or more
Combination：Ferrocene, stannous chloride and basic copper carbonate；The phase transfer catalyst is selected from following one or more
Combination：Tetramethyl ammonium chloride, tetrabutylammonium chloride, four octyl ammonium chlorides, methyl tricapryl ammonium chloride, ammonium bromide and tetraoctyl ammonium bromide,
Four hexyl ammonium chlorides, tetrabutylammonium iodide, tetrabutylammonium bromide and three-dodecyl methyl ammonium iodides；It is pungent preferably to be selected from methyl three
Ammonium chloride, and/or tetrabutylammonium bromide.
Accordingly, that the present invention provides a kind of technological processes is simple, reaction condition is mild, post-processing is easy and product purity
2,4,5- trifluoro benzene acetic acid preparation methods high, at low cost.
Specific implementation mode
Inventor after extensive and in-depth study, has found 2,4, the 5- trifluoros obtained for raw material with 2,4,5- trifluoromethyl anilines
Phenyl diazonium salt can obtain intermediate product by carrying out coupling reaction with substituted ethylene, then obtain 2,4,5- through hydrolyzing or aoxidizing
Trifluoro benzene acetic acid.
Main compound of the present invention or compound formula are as shown in Table 1：
Wherein, work as R2For hydrogen when, R1Substituent group selected from fat or aromatic structure containing 1 to 20 carbon atom；It preferably is selected from second
Alkenyl methyl ether, vinyl ethyl ether, vinyl-n-butyl ether or vinylacetate；
Work as R2When selected from chlorine, bromine, iodine, nitro, itrile group, aliphatic radical, fat or fragrant ether, R1Can also be selected from chlorine, bromine, iodine,
Nitro, itrile group, aliphatic radical, fat or fragrant ether, R1With R2It can be the same or different.
In one embodiment of the invention, R in the main compound or general formula that are related to aforementioned present invention1And R2
Variation, 2,4,5- trifluoro benzene acetic acids can be prepared by corresponding different route.
Route can be when using monosubstituted ethylene as coupled substrate：
Specifically, the first step, after 2,4,5- trifluoromethyl anilines and mixed in hydrochloric acid, sodium nitrite, which is added, makes acquisition structure such as formula
Intermediate state 2,4,5- trifluoro phenyl diazonium salts shown in A；
The 2 of acquisition, 4,5- trifluoro phenyl diazonium salts and monosubstituted ethylene are carried out coupling reaction, obtain structural formula B by second step
Shown in intermediate state；
Third walks, and after intermediate state material mixing shown in acid or alkali, catalyst and structural formula B, obtains shown in structural formula C
2,4,5- trifluoro phenylacetaldehydes；
2,4,5- trifluoro phenylacetaldehydes shown in structural formula C and pre-mixing agent are mixed, obtain structure as shown in formula I by the 4th step
2,4,5- trifluoro benzene acetic acids.
In the above-mentioned first step, the concentration of hydrochloric acid is 20-30v/v%；The sodium nitrite is the Asia of 35-45w/v%
Sodium nitrate aqueous solution；The reaction temperature is -10 DEG C -5 DEG C, preferably -5 DEG C -0 DEG C, more preferably 0 DEG C.
In above-mentioned second step, the monosubstituted ethylene is structure such as II compound represented, wherein R2For hydrogen, R1Selected from containing 1
To the fat of 20 carbon atoms or the substituent group of aromatic structure；Preferably be selected from methoxy ethylene, vinyl ethyl ether, vinyl-n-butyl ether,
Vinylacetate or methyl acrylate.
The coupling catalyst used in above-mentioned second step be selected from metallic catalyst, phase transfer catalyst, or combinations thereof；It is preferred that
The combination of metallic catalyst and phase transfer catalyst.The metallic catalyst is selected from following a combination of one or more：
Ferrocene, ferric acetyl acetonade, ferrous sulfate, copper powder, copper chloride, stannous chloride, copper sulphate, basic copper carbonate, cuprous iodide, nitre
Sour copper, Kocide SD and cuprous oxide；It preferably is selected from following a combination of one or more：Ferrocene, stannous chloride and
Basic copper carbonate；The phase transfer catalyst is selected from following a combination of one or more：Tetramethyl ammonium chloride, the tetrabutyl
Ammonium chloride, four octyl ammonium chlorides, methyl tricapryl ammonium chloride, ammonium bromide and tetraoctyl ammonium bromide, four hexyl ammonium chlorides, tetrabutylammonium iodide,
Tetrabutylammonium bromide and three-dodecyl methyl ammonium iodides；It preferably is selected from methyl tricapryl ammonium chloride, and/or tetrabutyl phosphonium bromide
Ammonium.
Temperature in above-mentioned second step is -10 DEG C -5 DEG C, preferably -5 DEG C -0 DEG C, more preferable 0 DEG C.
In one embodiment of the invention, it is by monosubstituted ethylene, coupling catalyst and reaction in above-mentioned second step
After solvent mixing, the diazonium salt system obtained in the first step is added dropwise wherein at above-mentioned temperature, rate of addition is slow, after dripping off
Heat preservation 5-10 hours.
In above-mentioned third step, the acid is 25-35v/v% hydrochloric acid, and the alkali is lithium hydroxide；The catalyst is selected from down
The a combination of one or more stated：Tetramethyl ammonium chloride, tetrabutylammonium chloride, four octyl ammonium chlorides, methyl trioctylphosphine chlorine
Change ammonium, ammonium bromide and tetraoctyl ammonium bromide, four hexyl ammonium chlorides, tetrabutylammonium iodide, tetrabutylammonium bromide and three-dodecyl methyl iodine
Change ammonium；It preferably is selected from methyl tricapryl ammonium chloride, and/or tetrabutylammonium bromide.
The temperature of above-mentioned third step is 0-60 DEG C, preferably 25-30 DEG C.
In one embodiment of the invention, above-mentioned third step is to mix acid or alkali, water, organic solvent and catalyst
It is added drop-wise to afterwards in intermediate state shown in the structural formula B obtained in second step, heat preservation obtains 2,4,5- trifluoro-benzene second after 20-30 hours
Aldehyde.
The oxidant used in above-mentioned 4th step is selected from sodium chlorite, sodium hypochlorite, hydrogen peroxide, Peracetic acid, m-chloro mistake
Oxybenzoic acid or sodium peroxydisulfate, preferably sodium chlorite.
In one embodiment of the invention, above-mentioned 4th step is that oxidant is added dropwise in 2,4,5- trifluoro phenylacetaldehydes,
After -10 DEG C -30 DEG C (preferably 0-5 DEG C) are reacted, adjusts pH and be larger than 10, be layered after oxidant is quenched, make water phase
PH is extracted after being less than 3, and organic phase is concentrated, rectifying, filtering, drying obtain structure 2,4,5- trifluoro-benzene as shown in formula I
Acetic acid.
The organic solvent tetrahydrofuran that is used in above-mentioned each step, acetonitrile, acetone, methanol, ethyl alcohol, dimethyl sulfoxide (DMSO) or they
Mixture；It is preferred that acetone.
Route can be when using together with disubstituted ethylene as coupled substrate：
Specifically, the first step, after 2,4,5- trifluoromethyl anilines and mixed in hydrochloric acid, sodium nitrite, which is added, makes acquisition structure such as formula
Intermediate state 2,4,5- trifluoro phenyl diazonium salts shown in A；
The 2 of acquisition, 4,5- trifluoro phenyl diazonium salts are carried out coupling reaction with together with disubstituted ethylene, obtain structure by second step
Intermediate shown in formula IV；
Third walks, and intermediate shown in structural formula IV is hydrolyzed to structure 2 as shown in formula I under strong acid or highly basic effect,
4,5- trifluoro benzene acetic acids.
In the above-mentioned first step, the concentration of hydrochloric acid is 20-30v/v%；The sodium nitrite is the Asia of 35-45w/v%
Sodium nitrate aqueous solution；The reaction temperature is -10 DEG C -5 DEG C, preferably -5 DEG C -0 DEG C, more preferably 0 DEG C.
In above-mentioned second step, it is described together with disubstituted ethylene be structure such as II compound represented, wherein R1And R2It is respectively selected from
Chlorine, bromine, iodine, nitro, itrile group, fat or fragrant ether, aliphatic radical；Described together with disubstituted ethylene is preferably 2- chloroacrylonitriles.
The coupling catalyst used in above-mentioned second step be selected from metallic catalyst, phase transfer catalyst, or combinations thereof；It is preferred that
The combination of metallic catalyst and phase transfer catalyst.The metallic catalyst is VI B to I B (left-to-right) in the periodic table of elements
The derivative of metal and they, such as copper powder, copper chloride, stannous chloride, cuprous bromide, copper sulphate, basic copper carbonate, iodate Asia
Copper, copper nitrate, Kocide SD, cuprous oxide, ferrocene, ferric acetyl acetonade, ferrous sulfate, iron chloride, frerrous chloride, protochloride
Cobalt, Cobalt dibromide, manganous chloride, manganese dibromide or their mixture；Wherein preferred stannous chloride, ferrocene；The phase turns
Shifting catalyst is tetramethyl ammonium chloride, tetrabutylammonium chloride, four octyl ammonium chlorides, methyl tricapryl ammonium chloride, four octyl brominations
Ammonium, four hexyl ammonium chlorides, tetrabutylammonium iodide, tetrabutylammonium bromide, three-dodecyl methyl ammonium iodides or their mixing
Object.
Temperature in above-mentioned second step is -10 DEG C -5 DEG C, preferably -5 DEG C -0 DEG C, more preferable 0 DEG C.
In one embodiment of the invention, being in above-mentioned second step will be together with disubstituted ethylene, coupling catalyst and anti-
After answering solvent to mix, the diazonium salt system obtained in the first step is added dropwise wherein at above-mentioned temperature, rate of addition is slow, drips off
Keep the temperature 5-10 hours afterwards.
In above-mentioned third step, the strong acid is 30% sulfuric acid, concentrated hydrochloric acid etc.；The highly basic is that 30% sodium hydroxide is water-soluble
Liquid, 30% potassium hydroxide aqueous solution etc..
The reaction temperature of above-mentioned third one-step hydrolysis is 0-60 DEG C, preferably 25-30 DEG C.
The organic solvent tetrahydrofuran that is used in above-mentioned each step, acetonitrile, acetone, methanol, ethyl alcohol, dimethyl sulfoxide (DMSO) or they
Mixture；It is preferred that acetone.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification
All features can be used in combination with any composition form, each feature disclosed in specification, any can provide it is identical,
The alternative characteristics of impartial or similar purpose replace.Therefore it is only impartial or similar spy except having special instruction, revealed feature
The general example of sign.
Main advantages of the present invention are：
Preparation method technological process provided by the invention is simple, reaction condition is mild, post-processing is easy and product purity is high,
It is at low cost.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.The unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as refers to 100
The weight of solute in the solution of milliliter.Unless otherwise defined, all professional and scientific terms used in text and this field are ripe
It is identical to practice meaning known to personnel.In addition, any method and material similar or impartial to described content all can be applied to
In the method for the present invention.The preferred methods and materials described herein are for illustrative purposes only.
Embodiment 1
The preparation of the chloro- 2- of 1- (2,4,5- trifluorophenyls)-ethylhexoate
2,4,5- trifluoromethyl aniline 147g (1mol) are added in 2L four-hole bottles, 24% hydrochloric acid 694g (4.56mol), heating is stirred
It mixes, is stirred 1 hour after system dissolved clarification, be cooled to 0 DEG C, 40% aqueous solution containing sodium nitrite (82.8g) is added dropwise, is protected after dripping off
1-2 hours warm, diazol prepares complete.Vinyl acetate 129g (1.5mol), ferrocene are mixed in another 2L four-hole bottles
18.57g (0.1mol), acetone 200g (2w/w), is cooled to 0 DEG C, and diazonium salt system, time for adding 2-3 hours, drop is slowly added dropwise
Keep the temperature 6-8 hour after finishing, filtering, organic phase 50g ethyl acetate and 200g normal heptanes recrystallize, and obtain the chloro- 2- of 1- (2,4,5-
Trifluorophenyl)-ethylhexoate crude product, yield 60%.
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).
Embodiment 2
The preparation of the chloro- 3- of 2- (2,4,5- trifluorophenyls)-methyl propionate
Vinyl acetate is replaced with 129.2g methyl acrylates, remaining is same as Example 1, and it is chloro- that reaction end obtains 2-
3- (2,4,5- trifluorophenyl)-methyl propionate crude product, yield 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).
Embodiment 3
The preparation of 2,2- bis- chloro- 3- (2,4,5- trifluorophenyls)-propionitrile
Vinyl acetate is replaced with 131.3g 2- chloroacrylonitriles, remaining is same as Example 1, and reaction terminates to obtain 2,2-
Two chloro- 3- (2,4,5- trifluorophenyl)-propionitrile crude products, yield 57%.
1H NMR(400MHz,CDCl3):δ7.41-7.18(m,1H),7.18-6.91(m,1H),3.78(s,2H).
Embodiment 4
The preparation of the chloro- 2- of 1- (2,4,5- trifluorophenyls)-ethylhexoate
2,4,5- trifluoromethyl aniline 147g (1mol) are added in 2L four-hole bottles, 24% hydrochloric acid 694g (4.56mol), heating is stirred
It mixes, is stirred 1 hour after system dissolved clarification, be cooled to 0 DEG C, 40% aqueous solution containing sodium nitrite (82.8g) is added dropwise, is protected after dripping off
1-2 hours warm, diazol prepares complete.Vinyl acetate 129g (1.5mol), basic carbonate are mixed in another 2L four-hole bottles
Copper 11.95g (0.054mol), tri-n-octyl methyl ammonium chloride 12g (0.03mol), sodium bicarbonate 42.76g (1mol), acetone 200g
(2w/w) is cooled to 0 DEG C, and diazonium salt system, time for adding 2-3 hours is slowly added dropwise, and drop keeps the temperature 6-8 hours after finishing, and filters, has
Machine mutually uses 50g ethyl acetate and 200g normal heptanes to recrystallize, and obtains the chloro- 2- of 1- (2,4,5- trifluorophenyl)-ethyl acetate crude product,
Yield 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).
Embodiment 5
The preparation of the chloro- 2- of 1- (2,4,5- trifluorophenyls)-ethylhexoate
Basic copper carbonate is replaced with 5.38g stannous chlorides, remaining is same as Example 4, and reaction terminates to obtain the chloro- 2- of 1-
(2,4,5- trifluorophenyl)-ethyl acetate crude product, yield 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).
Embodiment 6
The preparation of the chloro- 2- of 1- (2,4,5- trifluorophenyls)-ethylhexoate
Tri-n-octyl methyl ammonium chloride is replaced with 10g tetrabutylammonium bromide, remaining is same as Example 4, and reaction terminates to obtain
The chloro- 2- of 1- (2,4,5- trifluorophenyl)-ethyl acetate crude product, yield 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).
Embodiment 7
The preparation of 2,4,5- trifluoro phenylacetaldehydes
30% hydrochloric acid 132g (1.08mol), water 132g, acetone 160g, tricaprylmethyl chlorination are mixed in 2L four-hole bottles
Ammonium 3.66g (8.14mmol), 25-30 DEG C of stirring, is added dropwise the chloro- 2- of 1- (2,4,5- trifluorophenyl)-ethylhexoate crude product 98g
(0.27mol), insulation reaction for 24 hours, obtain 2,4,5- trifluoro-benzene acetaldehyde solutions, and external standard yield 85% direct plunges into next step.
Embodiment 8
The preparation of 2,4,5- trifluoro phenylacetaldehydes
30% hydrochloric acid is replaced with 26g lithium hydroxides, remaining is same as Example 7, and reaction terminates to obtain 2,4,5- trifluoro-benzenes
Acetaldehyde solution, external standard yield 76% direct plunge into next step.
Embodiment 9
The preparation of 2,4,5- trifluoro benzene acetic acids
The solution that 2,4,5- trifluoro phenylacetaldehyde crude product about 42g (0.22mol) will be contained is cooled to 0 DEG C, is added dropwise containing sub- chlorine
30% aqueous solution of sour sodium 40g (0.44mol), drips off for 2 hours, keeps the temperature 0-5 DEG C and reacts 4 hours.NaOH solids, which are added, in low temperature makes
System pH is more than 10, appropriate sodium sulfite solid is added, excessive oxidant is quenched, and toluene, layering is added, and 30% salt is added in water phase
Acid makes pH be less than 3, and toluene extraction is added, and organic phase is concentrated under reduced pressure into no fraction, and fraction is collected in the residual rectifying of kettle, and fraction is beaten with DCM
Slurry, filters to obtain filter cake, and 2,4,5- trifluoro benzene acetic acid 33g, content 99%, yield 80% are obtained after drying.
1H NMR(400MHz,CDCl3):δ7.20-7.02(m,1H),7.02-6.85(m,1H),3.67(s,2H).
Embodiment 10
The preparation of 2,4,5- trifluoro benzene acetic acids
Sodium chlorite is replaced with 76.7g metachloroperbenzoic acids, remaining is same as Example 9, and reaction terminates to obtain 2,4,
5- trifluoro benzene acetic acid crude products, content 99%, yield 78%.
1H NMR(400MHz,CDCl3):δ7.20-7.02(m,1H),7.02-6.85(m,1H),3.67(s,2H).
Embodiment 11
The preparation of 2,4,5- trifluoro phenylacetaldehydes
2,4,5- trifluoromethyl aniline 147g (1mol) are added in 2L four-hole bottles, 24% hydrochloric acid 694g (4.56mol), heating is stirred
It mixes, is stirred 1 hour after system dissolved clarification, be cooled to 0 DEG C, 40% aqueous solution containing sodium nitrite (82.8g) is added dropwise, is protected after dripping off
1-2 hours warm, diazol prepares complete.Mixed ethylene base ether 108.2g (1.5mol), ferrocene in another 2L four-hole bottles
18.57g (0.1mol), acetone 200g (2w/w), is cooled to 0 DEG C, and diazonium salt system, time for adding 2-3 hours, drop is slowly added dropwise
6-8 hours are kept the temperature after finishing, the 1- generated in system (2- chloro-2-ethoxies) -2,4,5- trifluoro-benzenes are gradually hydrolyzed to 2,4,5- tri-
Fluorobenzene acetaldehyde, extending soaking time keeps conversion complete, and methyl tertiary butyl ether(MTBE) extraction is concentrated under reduced pressure, obtains 2,4,5- trifluoro-benzene second
Aldehyde crude product, external standard yield 42% direct plunge into next step.
Embodiment 12
The preparation of 2,4,5- trifluoro benzene acetic acids
2,4,5- trifluoro phenylacetaldehyde crude product 42g (0.22mol), tetrahydrofuran 200g, 30% salt are mixed in bis- mouthfuls of bottles of 1L
Sour 26.8g (0.22mol) is cooled to 0 DEG C, and 30% aqueous solution containing sodium chlorite 40g (0.44mol) is added dropwise, and drips within 2 hours
It is complete, it keeps the temperature 0-5 DEG C and reacts 4 hours, NaOH solids, which are added, in low temperature makes system pH be more than 10, and appropriate sodium sulfite solid is added and is quenched
Toluene is added in excessive oxidant, and layering, 30% hydrochloric acid, which is added, in water phase makes pH be less than 3, and toluene extraction is added, and organic phase decompression is dense
It is reduced to no fraction, fraction is collected in the residual rectifying of kettle, and fraction is beaten with DCM, filters to obtain filter cake, and 2,4,5- trifluoro-benzene second are obtained after drying
Sour 33g, content 99%, yield 75%.
1H NMR(400MHz,CDCl3):δ7.20-7.02(m,1H),7.02-6.85(m,1H),3.67(s,2H).
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content model of the present invention
It encloses, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete
Entity or method also or a kind of equivalent change, will if identical with defined in the right of application
It is considered as being covered by among the right.
Claims (10)
1. a kind of preparation method of structure such as I compound represented of formula, 2,4,5- trifluoro benzene acetic acid, which is characterized in that the method
Including step：
(1) by structure as 2,4,5- trifluoros phenyl diazonium salt shown in formula A and structure substituted ethylene as shown in formula II are coupled
Reaction, obtains intermediate；
(2) intermediate is made to obtain structure 2,4,5- trifluoro benzene acetic acids as shown in formula I through hydrolyzing or aoxidizing；
The intermediate includes structure such as IV compound represented of formula or structure the 2,4,5- trifluoros phenylacetaldehyde as shown in formula C；
Wherein, R1Substituent group, chlorine, bromine, iodine, nitro, itrile group, fat selected from fat or aromatic structure containing 1 to 20 carbon atom
Base；R2Selected from hydrogen, chlorine, bromine, iodine, nitro, itrile group, aliphatic radical, fat or fragrant ether.
2. preparation method as described in claim 1, which is characterized in that R1For fat or aromatic structure containing 1 to 20 carbon atom
Substituent group；R2For hydrogen；The structure such as II compound represented preferred vinyl methyl ether of formula, vinyl ethyl ether, vinyl fourth
Ether, vinylacetate or methyl acrylate.
3. preparation method as described in claim 1, which is characterized in that R1And R2It is respectively selected from the fat containing 1 to 20 carbon atom
Or fragrant ether, chlorine, bromine, iodine, nitro, itrile group or aliphatic radical；The structure such as II compound represented of formula is preferably together with two chloroethenes
Alkene, 2- chloroacrylonitriles or 1,1- dimethoxy ethylene.
4. preparation method as claimed in claim 2, which is characterized in that the method includes the steps：
(1) after 2,4,5- trifluoromethyl anilines and hydrochloric acid are at salt as shown in formula III by structure, sodium nitrite is added, obtains structure such as formula
2,4,5- trifluoros phenyl diazonium salt shown in A；
(2) by structure as 2,4,5- trifluoros phenyl diazonium salt shown in formula A and structure substituted ethylene as shown in formula II are coupled
Reaction, obtains structure intermediate as shown in formula IV；
(3) structure intermediate as shown in formula IV is made to obtain structure 2,4,5- trifluoros phenylacetaldehyde as shown in formula C through hydrolysis；
(4) structure 2,4,5- trifluoros phenylacetaldehyde as shown in formula C is oxidized obtains structure 2,4,5- trifluoro-benzenes second as shown in formula I
Acid；
5. preparation method as claimed in claim 4, which is characterized in that oxidant is selected from sodium chlorite, hypochlorous acid in step (4)
Sodium, hydrogen peroxide, Peracetic acid, metachloroperbenzoic acid or sodium peroxydisulfate preferably are selected from sodium chlorite or metachloroperbenzoic acid.
6. preparation method as claimed in claim 4, which is characterized in that the reaction temperature that in step (1) prepared by diazol is -10
DEG C -5 DEG C, preferably -5 DEG C -0 DEG C；The reaction temperature being coupled in step (2) is -10 DEG C -5 DEG C, preferably -5 DEG C -0 DEG C；Step
(3) reaction temperature in is 0-60 DEG C, preferably 25-30 DEG C；Reaction temperature in step (4) is -10 DEG C -30 DEG C, preferably
0-5℃。
7. preparation method as claimed in claim 3, which is characterized in that the method includes the steps：
(1) after 2,4,5- trifluoromethyl anilines and hydrochloric acid are at salt as shown in formula III by structure, sodium nitrite is added, obtains structure such as formula
2,4,5- trifluoros phenyl diazonium salt shown in A；
(2) by structure as 2,4,5- trifluoros phenyl diazonium salt shown in formula A and structure substituted ethylene as shown in formula II are coupled
Reaction, obtains structure intermediate as shown in formula IV；
(3) structure intermediate as shown in formula IV is made to obtain structure 2,4,5- trifluoro benzene acetic acids as shown in formula I through hydrolysis.
8. preparation method as claimed in claim 7, which is characterized in that hydrolyst is 30% sulfuric acid, dense salt in step (3)
Acid, 30% sodium hydrate aqueous solution or 30% potassium hydroxide aqueous solution.
9. preparation method as claimed in claim 7, which is characterized in that the reaction temperature that in step (1) prepared by diazol is -10
DEG C -5 DEG C, preferably -5 DEG C -0 DEG C；The reaction temperature being coupled in step (2) is -10 DEG C -5 DEG C, preferably -5 DEG C -0 DEG C；Step
(3) reaction temperature in is 0-60 DEG C, preferably 25-30 DEG C.
10. such as claim 4-9 any one of them preparation methods, which is characterized in that the coupling catalyst used in step (2)
Selected from metallic catalyst, phase transfer catalyst, or combinations thereof；It is preferred that the combination of metallic catalyst and phase transfer catalyst；It is described
Metallic catalyst is selected from following a combination of one or more：Ferrocene, ferric acetyl acetonade, ferrous sulfate, copper powder, chlorination
Copper, stannous chloride, copper sulphate, basic copper carbonate, cuprous iodide, copper nitrate, Kocide SD and cuprous oxide；It preferably is selected from following
A combination of one or more：Ferrocene, stannous chloride and basic copper carbonate；The phase transfer catalyst is selected from following
A combination of one or more：Tetramethyl ammonium chloride, tetrabutylammonium chloride, four octyl ammonium chlorides, methyl trioctylphosphine chlorination
Ammonium, ammonium bromide and tetraoctyl ammonium bromide, four hexyl ammonium chlorides, tetrabutylammonium iodide, tetrabutylammonium bromide and three-dodecyl methyl iodate
Ammonium；It preferably is selected from methyl tricapryl ammonium chloride, and/or tetrabutylammonium bromide.
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