CN104080791B - 分离和使用(4-氯-2-氟-3-取代的-苯基)硼酸酯的方法 - Google Patents
分离和使用(4-氯-2-氟-3-取代的-苯基)硼酸酯的方法 Download PDFInfo
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- CN104080791B CN104080791B CN201280068666.XA CN201280068666A CN104080791B CN 104080791 B CN104080791 B CN 104080791B CN 201280068666 A CN201280068666 A CN 201280068666A CN 104080791 B CN104080791 B CN 104080791B
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- 238000000034 method Methods 0.000 title claims abstract description 37
- -1 4-substituted-phenyl Chemical group 0.000 title claims description 124
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 title description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 75
- 239000000203 mixture Substances 0.000 claims abstract description 45
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 38
- 239000007787 solid Substances 0.000 claims abstract description 37
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 28
- 229910003002 lithium salt Inorganic materials 0.000 claims abstract description 22
- 159000000002 lithium salts Chemical class 0.000 claims abstract description 22
- DKTXXUNXVCHYDO-UHFFFAOYSA-N phenoxyborinic acid Chemical class OBOC1=CC=CC=C1 DKTXXUNXVCHYDO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 235000011089 carbon dioxide Nutrition 0.000 claims abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 16
- 239000011737 fluorine Substances 0.000 claims abstract description 15
- 238000001556 precipitation Methods 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000000376 reactant Substances 0.000 claims description 22
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 238000010612 desalination reaction Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- SCDNBGFXFOSCIN-UHFFFAOYSA-N [Li].COC(O)=O Chemical compound [Li].COC(O)=O SCDNBGFXFOSCIN-UHFFFAOYSA-N 0.000 claims description 9
- 208000035126 Facies Diseases 0.000 claims description 7
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- NHNUFAASKXPOQA-UHFFFAOYSA-N (3-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound C(C)(=O)NC=1C(=C(C=CC1)[As](O)(=O)O)O NHNUFAASKXPOQA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 230000005587 bubbling Effects 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 3
- QASFEHCRPLPGES-UHFFFAOYSA-N 1-chloro-3-fluoro-2-methoxybenzene Chemical compound COC1=C(F)C=CC=C1Cl QASFEHCRPLPGES-UHFFFAOYSA-N 0.000 claims description 3
- WHXBFLPPIISOMO-UHFFFAOYSA-N [B]C1=CC=C(F)C(OC)=C1 Chemical compound [B]C1=CC=C(F)C(OC)=C1 WHXBFLPPIISOMO-UHFFFAOYSA-N 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- LUJMSRVFSBMEOY-UHFFFAOYSA-N (4-fluoro-3-methoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC=C1F LUJMSRVFSBMEOY-UHFFFAOYSA-N 0.000 claims description 2
- JDXYQLIQPZKYLH-UHFFFAOYSA-N CC=1C(=C(C=CC1NC(C)=O)[As](O)(O)=O)O Chemical compound CC=1C(=C(C=CC1NC(C)=O)[As](O)(O)=O)O JDXYQLIQPZKYLH-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- SEQIFORDAFGMLW-UHFFFAOYSA-N dimethoxy-(2-methoxyphenyl)borane Chemical class COB(OC)C1=CC=CC=C1OC SEQIFORDAFGMLW-UHFFFAOYSA-N 0.000 claims description 2
- MLSKXPOBNQFGHW-UHFFFAOYSA-N methoxy(dioxido)borane Chemical compound COB([O-])[O-] MLSKXPOBNQFGHW-UHFFFAOYSA-N 0.000 claims description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 239000008346 aqueous phase Substances 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract 8
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 45
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 14
- 229910052744 lithium Inorganic materials 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 239000007789 gas Substances 0.000 description 9
- 229960004979 fampridine Drugs 0.000 description 6
- 150000001642 boronic acid derivatives Chemical class 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 238000006138 lithiation reaction Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001555 benzenes Chemical class 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- DELPSTRBSBMRBI-UHFFFAOYSA-N CC(CCC)=O.C1=CC=CC=C1 Chemical compound CC(CCC)=O.C1=CC=CC=C1 DELPSTRBSBMRBI-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- XPPWLXNXHSNMKC-UHFFFAOYSA-N phenylboron Chemical compound [B]C1=CC=CC=C1 XPPWLXNXHSNMKC-UHFFFAOYSA-N 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 2
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XELVYABXHBMJRZ-UHFFFAOYSA-N 2-amino-6-chloropyridine-4-carboxylic acid Chemical compound NC1=CC(C(O)=O)=CC(Cl)=N1 XELVYABXHBMJRZ-UHFFFAOYSA-N 0.000 description 1
- 239000005468 Aminopyralid Substances 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- VPOMGICCPSHCOF-UHFFFAOYSA-N ClC1=NC=CC(=C1)C(=O)O.CC=1C(=C(C(=CC1)NC(C)=O)[As](O)(O)=O)O Chemical compound ClC1=NC=CC(=C1)C(=O)O.CC=1C(=C(C(=CC1)NC(C)=O)[As](O)(O)=O)O VPOMGICCPSHCOF-UHFFFAOYSA-N 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical class OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- VPCAAUUIFCAFRZ-UHFFFAOYSA-N butylalumane Chemical compound CCCC[AlH2] VPCAAUUIFCAFRZ-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical group [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical group CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
分离4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯的方法包括将二氧化碳气体或二氧化碳固体(干冰)加入到包含4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯,惰性有机溶剂,和至少一种锂盐的溶液中,以使所述至少一种锂盐与二氧化碳气体或二氧化碳固体(干冰)反应,形成包含所述4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯、所述惰性有机溶剂和沉淀固体的混合物。所述沉淀固体可从混合物中除去。本发明还公开了使用4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯制备甲基‑4‑氨基‑3‑氯‑6‑(4‑氯‑2‑氟‑3‑取代的‑苯基)吡啶‑2‑羧酸酯的方法。本发明还公开了由分离4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯的方法中的一种制备的4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯,其中可获得收率大于或等于约90%的所述4‑氯‑2‑氟‑3‑取代的‑苯基硼酸酯。
Description
优先权声明
本申请要求2011年12月30日提交的,名称为“分离和使用(4-氯-2-氟-3-取代的-苯基)硼酸酯的方法”的美国临时专利申请61/582,175的优先权。
技术领域
本申请公开的实施方式涉及分离4-氯-2-氟-3-取代的-苯基硼酸酯的方法和使用4-氯-2-氟-3-取代的-苯基硼酸酯的方法。本申请公开的实施方式还涉及分离和使用4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯(PBA-diMe)的方法。
背景技术
4-氯-2-氟-3-甲氧基苯基硼酸酸(PBA)和2-(4-氯-2-氟-3-甲氧基苯基)-1,3,2-二氧硼杂(PBE)在6-(多-取代芳基)-4-氨基吡啶-2-羧酸酯和2-(多-取代芳基)-6-氨基-4-吡啶羧酸(其可用于除草剂中间物)的合成中是有用的。
通过如下方法可合成PBA:使2-氯-6-氟sole与三甲基硼酸酯B(OMe)3和n-丁基铝反应,将含水碱加入到反应混合物中,用乙腈稀释反应混合物,并用盐酸酸化反应混合物。可用1,3-丙二醇酯化PBA形成PBE。
通过分离和使用PBA或另一4-氯-2-氟-3-取代的-苯基硼酸的前体来高效合成6-(多-取代芳基)-4-氨基吡啶-2-羧酸酯和2-(多-取代芳基)-6-氨基-4-吡啶羧酸能够减少单元操作将是令人期望的。
发明内容
本发明公开的实施方式包括分离4-氯-2-氟-3-取代的-苯基硼酸酯的方法,包括将二氧化碳气体或二氧化碳固体(干冰)加入到包含4-氯-2-氟-3-取代的-苯基硼酸酯、惰性有机溶剂和至少一种锂盐的溶液中,使所述至少一种锂盐与二氧化碳气体反应,形成包含4-氯-2-氟-3-取代的-苯基硼酸酯、惰性有机溶剂和沉淀固体的混合物。所述沉淀固体可从混合物中除去。
本发明公开的另一实施方式包括合成和分离4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯的方法,包括将含有2-氯-6-氟苯甲醚和1,2-二甲氧基乙烷的溶液与n-丁基铝接触,形成包含6-氯-2-氟-3-锂苯甲醚和1,2-二甲氧基乙烷的反应混合物。所述反应混合物可以与硼酸三甲酯接触以形成包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷,和至少一种锂盐的盐化苯基硼酸酯溶液。二氧化碳气体或二氧化碳固体(干冰)可引入到所述盐化苯基硼酸酯溶液中以形成包含所述4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷和甲基碳酸锂的混合物。所述甲基碳酸锂可分离以形成包含所述4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯和1,2-二甲氧基乙烷的脱盐苯基硼酸酯溶液。
本发明公开的又一实施方式包括使用4-氯-2-氟-3-取代的-苯基硼酸酯的方法,包含将4-氯-2-氟-3-取代的-苯基硼酸酯与4-乙酰氨基-3,6-二氯吡啶甲酸酯,例如4-乙酰氨基-3,6-二氯甲基吡啶-2-甲酸甲酯反应,以制备6-(4-氯-2-氟-3-取代的-苯基)-4-氨基吡啶甲酸酯,例如,4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-甲酸甲酯。
本发明公开的一特定实施方式包括由如下方法制备的4-氯-2-氟-3-取代的-苯基硼酸酯,所述方法将二氧化碳气体或二氧化碳固体(干冰)加入到包含4-氯-2-氟-3-取代的-苯基硼酸酯,惰性有机溶剂和至少一种锂盐的溶液中,使所述至少一种锂盐与二氧化碳气体反应,形成包含4-氯-2-氟-3-取代的-苯基硼酸酯,惰性有机溶剂和沉淀固体的混合物。然后可以将所述沉淀固体从混合物中除去。所述4-氯-2-氟-3-取代的-苯基硼酸酯的收率大于或等于约90%。
具体实施方式
本申请公开了分离4-氯-2-氟-3-取代的-苯基硼酸酯,例如PBA-diMe的方法。所述4-氯-2-氟-3-取代的-苯基硼酸酯可以通过如下方式合成:将包含1-氯-3-氟-2-取代苯和惰性有机溶剂的溶液与烷基锂和亲电的硼酸衍生物反应,以形成包含所述4-氯-2-氟-3-取代的-苯基硼酸酯,惰性有机溶剂和至少一种锂盐的盐化苯基硼酸酯溶液。通过将苯基硼酸酯溶液暴露于二氧化碳(CO2)气体或二氧化碳固体(干冰),可从所述至少一种锂盐中分离所述4-氯-2-氟-3-取代的-苯基硼酸酯。接着过滤,可得到包含在惰性有机溶剂中的4-氯-2-氟-3-取代的-苯基硼酸酯的脱盐苯基硼酸酯溶液。脱盐苯基硼酸酯溶液可直接用于进一步的反应中,例如Suzuki偶合反应,以制备其他的化合物,例如6-(4-氯-2-氟-3-取代的-苯基)-4-氨基吡啶甲酸酯,例如,甲基-4-氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯。
由1-氯-3-氟-2-取代苯制备4-氯-2-氟-3-取代的-苯基硼酸酯的反应方案示出如下:
其中X是F,OR1,或NR2R3,Y是H或F,每个R1,R2和R3独立地为甲基,乙基,丙基或丁基,和M是硼酸衍生物。反应方案详细描述如下。
可将烷基锂加入或引入到包含1-氯-3-氟-2-取代苯的溶液中,以促使1-氯-3-氟-2-取代苯和烷基锂之间发生锂化反应,形成包含锂化的1-氯-3-氟-2-取代苯的反应混合物。在至少一些实施方式中,所述1-氯-3-氟-2-取代苯是2-氯-6-氟苯甲醚(2,6-CFA)。1-氯-3-氟-2-取代苯可由常规技术制备,这里不再赘述。烷基锂可是包含锂和烷基官能团(即,直链,支链,或环形结构)的任何化合物,该烷基官能团为例如,甲基,乙基,1-甲基乙基,丙基,环丙基,丁基,1,1-二甲基乙基,环丁基,1-甲基丙基,或己基。借助于非限定的实施方式,烷基锂可包括甲基锂,n-丁基锂(n-BuLi),s-丁基锂,t-丁基锂,或丙基锂。在一种或多种实施方式中,烷基锂是n-BuLi。烷基锂可购自众多来源,包括但不限于,Sigma-Aldrich CO.(St.Louis,MO)。在1-氯-3-氟-2-取代苯是2,6-CFA的实施方式中,烷基锂是n-BuLi,锂化的1-氯-3-氟-2-取代苯可以是6-氯-2-氟-3-锂苯甲醚(Li-2,6-CFA)。
锂化反应可在惰性有机溶剂中进行,其中1-氯-3-氟-2-取代苯至少部分可溶。在一种或多种实施方式中,1-氯-3-氟-2-取代苯至少大体上溶于惰性有机溶剂中。惰性有机溶剂可包括,但不限定于,C5-C8烃(即,直链,支链,或环形结构的烃),例如戊烷,己烷,环己烷,异辛烷,醚(例如,乙醚,四氢呋喃,二噁烷,二醇醚包括1,2-二甲氧基乙烷),或其组合物。在至少一些实施方式中,惰性有机溶剂是1,2-二甲氧基乙烷(DME)。
相对1-氯-3-氟-2-取代苯可用至少一个摩尔当量的烷基锂。相对1-氯-3-氟-2-取代苯化合物,可加入稍过量的烷基锂,例如相对于1-氯-3-氟-2-取代苯过量约1%至约10%摩尔,或相对于1-氯-3-氟-2-取代苯过量约2%至约5%摩尔。锂化反应可在无水条件,大气压或高于大气压,和低于或等于-30℃的温度,优选低于-50℃,例如低于约-65℃下进行。反应混合物可搅拌(例如,通过搅动、超声搅拌、摇动密封容器)至足够量的时间,以促使1-氯-3-氟-2-取代苯在与氟取代基键合的碳原子(C3)和与Y基团键合的另一个碳原子(C5)之间的位点(C4)进行去质子化。锂化反应可在惰性气氛,例如在氮气(N2)气氛下进行。
亲电的硼酸衍生物可被加入或引入到反应混合物中与锂化的1-氯-3-氟-2-取代苯反应或接触,形成包括(4-氯-2-氟-3-取代的-苯基)硼酸酯,惰性有机溶剂和至少一种锂盐,例如甲氧基锂的盐化苯基硼酸酯溶液。亲电硼酸衍生物可是三烷基硼酸酯,例如三甲基硼酸酯(B(OMe)3),三异丙基硼酸酯(B(OiPr)3)或三乙基硼酸酯(B(OEt)3)。在至少一些实施方式中,亲电硼酸衍生物是(B(OMe)3)。在亲电硼酸衍生物是(B(OMe)3)的实施方式中,锂化的1-氯-3-氟-2-取代苯是Li-2,6-CFA,4-氯-2-氟-3-取代的-苯基硼酸酯可以是4-氯-2-氟-3-取代的-苯基硼酸二甲基酯(PBA-diMe)。可缓慢加入亲电硼酸衍生物,同时保持反应混合物的温度低于或等于约-65℃。反应混合物可被搅拌到足够量的时间以促使亲电硼酸衍生物与锂化的1-氟-2-取代-3-氯苯反应。至反应结束,盐化的苯基硼酸酯溶液可具有从约20℃至约25℃的温度范围(例如,环境温度)。
为了分离4-氯-2-氟-3-取代的-苯基硼酸酯,CO2气体可被加入或引入到盐化的苯基硼酸酯溶液(例如,使CO2鼓泡通过盐化的苯基硼酸酯溶液)或加入二氧化碳固体(干冰),以与所述至少一种锂盐反应形成包括沉淀固体,例如甲基碳酸锂的混合物。沉淀固体可被充分分离或除去(例如,对混合物过滤),以形成包括在惰性有机溶剂中的4-氯-2-氟-3-取代的-苯基硼酸酯的脱盐苯基硼酸酯溶液。在至少一些实施方式中,脱盐的苯基硼酸酯溶液包括DME中的PBA-diMe。4-氯-2-氟-3-取代的-苯基硼酸酯可保持在脱盐的苯基硼酸酯溶液中和可直接用于随后的反应中而无需额外浓缩或干燥。任选地,脱盐的苯基硼酸酯溶液可以在减压下脱除溶剂或通过结晶分离出4-氯-2-氟-3-取代的-苯基硼酸酯固体。
以下详细的反应方案说明2,6-CFA至PBA-diMe的典型转化:
在低于或等于约-65℃的温度下,2,6-CFA可与无水DME中的n-BuLi反应形成包含Li-2,6-CFA的反应混合物。B(OMe)3可被加入或引入到反应混合物中,其中它可与Li-2,6-CFA反应或接触,形成包含PBA-diMe,DME和至少一种锂盐的盐化苯基硼酸酯溶液。可将CO2鼓泡通过盐化的苯基硼酸酯溶液,以与所述至少一种锂盐反应或接触,形成包含甲基碳酸锂,PBA-diMe和DME的混合物。所述混合物可被过滤以充分除去甲基碳酸锂,形成包含在DME中的PBA-diMe的脱盐苯基硼酸酯溶液。PBA-diMe的收率可大于或等于约90%,例如大于或等于约95%,或大于或等于约97%。
脱盐的苯基硼酸酯溶液或4-氯-2-氟-3-取代的-苯基硼酸酯固体可用于其他的化学反应中,例如Suzuki偶合反应。借助于非限定的实施方式,脱盐的苯基硼酸酯溶液(或4-氯-2-氟-3-取代的-苯基硼酸酯固体)可与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯(即,乙酰化氨基吡啶甲基酯(aminopyralidmethyl ester)-AcAP-Me)发生交叉偶合反应,以制备或形成甲基4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯,例如甲基4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-羧酸酯(Ac729-Me)。交叉偶合反应可在钯催化剂,配位体(ligand)和碱的存在下发生。在至少一些实施方式中,钯催化剂是醋酸钯(II)(Pd(OAc)2),碱是碳酸钾(K2CO3)水溶液,配位体是三苯基膦(PPh3)。AcAP-Me可以固体形式使用或可以提供于溶剂中,该溶剂例如MIBK,MeCN,EtOAc,甲苯,水,或其组合物。在可选择的实施方式中,PBA-diMe可用于制备2-(4-氯-2-氟-3-甲氧基苯基)-6-氨基-4-吡啶羧酸。PBA-diMe的偶合配对物将是甲基6-乙酰氨基-2-氯吡啶-4-羧酸盐或其未受保护的变型6-氨基-2-氯吡啶-4-羧酸。
钯催化剂,配位体和碱可被加入到包含AcAP-Me和脱盐苯基硼酸酯溶液(或4-氯-2-氟-3-取代的-苯基硼酸酯固体)的去氧混合物中,形成偶合反应混合物。偶合反应混合物可在40℃至70℃的温度范围下搅拌至足够量的时间以完成交叉偶合反应和形成具有有机相的第三多相溶液,该有机相包括6-(4-氯-2-氟-3-取代的-苯基)-4-氨基吡啶甲酸酯,例如,甲基-4-氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯。钯催化剂可被除去(例如,将第三多相溶液暴露至硅藻土中),有机相可被分离或萃取。在偶合反应混合物包含PBA-diMe和AcAP-Me的实施方式中,Ac729-Me的收率可大于约85%,例如大于约90%,或大于约95%。
与用(4-氯-2-氟-3-取代的-苯基)硼酸(例如,PBA)或用4-氯-2-氟-3-取代的-苯基硼酸酯(例如,PBE)相比,用4-氯-2-氟-3-取代的-苯基硼酸酯与AcAP-Me发生偶合反应来制备6-(4-氯-2-氟-3-取代的-苯基)-4-氨基吡啶甲酸酯,例如,甲基-4-氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯是令人满意的,因为能够使得制备6-(4-氯-2-氟-3-取代的-苯基)-4-氨基吡啶甲酸酯,例如,甲基-4-氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯需要较少的单元操作(例如,可以省略通常与诸如形成PBA或PBE有关的操作,例如水解,第一相分离,有机物洗涤,第二相分离,酸化和萃取)。然而,用包含4-氯-2-氟-3-取代的-苯基硼酸酯、惰性有机溶剂和所述至少一种锂盐的盐化苯基硼酸酯溶液与AcAP-Me发生偶合反应来制备甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯时收率很低(例如,小于5%)。不受特定理论限制,据信该很的低收率源于所述至少一种锂盐的存在引起的水解反应。有利地,将CO2气体或CO2固体(干冰)加入或引入到盐化苯基硼酸酯溶液中以促使除去至少一种锂盐,使得能够通过脱盐苯基硼酸酯溶液与AcAP-Me之间的偶合反应来以良好的收率(例如,大于或等于85%)制备甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯。
在任何水加入或引入到惰性有机溶剂前,将CO2气体或CO2固体(干冰)加入或引入到盐化苯基硼酸酯溶液中以分离在惰性有机溶剂中的4-氯-2-氟-3-取代的-苯基硼酸酯还可提供回收或重新获得惰性有机溶剂的机会。一般来说,为了用于1-氯-3-氟-2-取代苯和烷基锂之间的锂化反应,惰性有机溶剂保持基本上无水(通常称为“干燥的”)。由于至少一些惰性有机溶剂,例如DME,基本上与水混溶,因此将该惰性有机溶剂与水分离会很困难和事与愿违的。合成4-氯-2-氟-3-取代的-苯基硼酸或4-氯-2-氟-3-取代的-苯基硼酸酯的方法通常将惰性有机溶剂和水接触(例如,经由含水碱的(4-氯-2-氟-3-取代的-苯基)硼酸酯水解过程中)。相反,用CO2气体或CO2固体(干冰)分离惰性有机溶剂中的4-氯-2-氟-3-取代的-苯基硼酸酯和使用脱盐苯基硼酸酯溶液制备6-(4-氯-2-氟-3-取代的-苯基)-4-氨基吡啶甲酸酯,例如,甲基-4-氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯,可防止惰性有机溶剂和水接触,至少能更有效的回收或重复利用惰性有机溶剂以用于其他锂化过程。
下面的实施例用于详细解释本发明的实施方式。这些实施例不作为对本发明范围详尽的或排他性的解释。
实施例
实施例1:合成,分离和使用PBA-diMe
在500mL瓶中制备含2,6-CFA(15.2g,93.5mmol)的无水DME(118mL)溶液。加入分子筛去除水分,采用Karl Fisher滴定法测量水含量,确保水含量<100ppm(测定值为80ppm)。溶液通过隔片口(septum port)转移到反应器中并置换隔膜。启动氮气垫(pad)。启动搅拌器,并设置在270rpm。反应器下方的杜瓦瓶中充满一半的丙酮溶剂。慢慢加入干冰块。当浴中溶剂冷却时,加入更多的溶剂,使浴中溶剂的液位在反应器中2,6-CFA的液位之上。在实验过程中,周期性加入干冰块,保持溶剂浴温度在-76℃。允许2,6-CFA溶液的温度冷却至-72℃。将在己烷(2.5M,41.5ml)中的n-BuLi装载到60ml的塑料注射器中,并固定在注射器泵上。以0.7ml/min的添加速度启动注射器泵。64分钟后完成n-BuLi的添加。反应溶液保持在-72℃温度达57分钟。将B(OMe)3(13.1g,14.06ml)装载到24ml的塑料注射器中,并固定在注射器泵上。提高搅拌器的速率至302rpm。当反应溶液处于-72℃时,以0.4ml/min的添加速度启动注射器泵。40分钟后完成硼酸酯的添加。在220rpm的搅拌下,反应溶液留置在冷浴中过夜。收集到总共153g含有PBA-diMe的反应溶液。用内标物使用GC法定量分析溶液中PBA-diMe的含量。计算得到98%的2,6-CFA转化为PBA-diMe和2%的初始2,6-CFA未转化。在反应器中在18℃搅拌PBA-diMe溶液。启动搅拌器,并设置在294rpm。通过1/4英寸(0.635cm)的玻璃管,将小气阀瓶中的CO2气体慢慢鼓入到溶液内至42分钟以上。将溶液加热至21℃。总计加入7.2g(1.5当量)的CO2气体。混合物很浑浊,带有细小的白色固体。用1#Whatman滤纸和吸水器(water aspirator)在7.5cm的Buchner漏斗中过滤混合物(153g)。除去细小的白色固体(甲基碳酸锂)。用3.5g的己烷洗涤所述固体。收集到141g滤液。收集到3.5g干燥的白色固体。PBA-diMe滤液置于装有吸水器,干冰阱和顶部接收器的旋转蒸发仪上的500ml圆底烧瓶中。在浴温25℃时启动旋转蒸发仪。真空范围从45mmHg降至15mmHg,最终浴温为31℃。17分钟后收集到顶部溶剂106.5g,瓶底残余物30.1g。经GC法分析得出,瓶底物含有59.4%重量的PBA。这个过程获得97%的PBA回收。一些PBA-diMe滤液用于Suzuki的偶合反应中。向配有冷凝器、热电偶温度探针、磁搅拌棒和N2入口的50ml三颈圆底烧瓶中加入AcAP-Me(3.0g,11.4mmol)。向圆底烧瓶中加入PPh3(90mg,0.342mmol),接着加入四丁基溴化铵(TBAB,37mg,0.114mmol)。在氮气氛下将固体Pd(OAc)2(26mg,0.114mmol)加入到圆底烧瓶中。边搅拌边用N2对溶剂甲苯(16.3mL)和乙腈(3.0mL)各独自吹扫30分钟,然后加入到反应混合物中。搅拌反应混合物5分钟,之后加入K2CO3水溶液(22.8%,17mL,预先用N2吹扫30分钟)。加热反应混合物至65℃,并搅拌2小时。2小时后,由GC法对反应物取样,确定反应的完成。一旦反应完成,将混合物转移至加热的分液漏斗和相分离。用内标物(苯戊酮)使用GC法对有机相取样,得到转化率为89%的Ac729-Me(3.55g,81%)。
实施例2:对比例
称取2,6-CFA(144.5g,900mmol)直接加入到2L的带有顶部机械搅拌器,热电偶温度探针和N2入口的三颈圆底烧瓶中。将无水DME(1125mL)加入到圆底烧瓶。用干冰/丙酮浴将反应冷却至-78℃。一旦反应达到约-77℃时,用注射器泵缓慢逐滴加入n-BuLi(425mL,1035mmol,2.5M,在己烷中)至1小时以上。在添加过程中达到的最高温度为-68.8℃。完成n-BuLi的添加后,在-73.5℃下搅拌反应1小时。1小时后,用加料漏斗逐滴加入B(OMe)3(10.5mL,93.42mmol)至约1小时以上。在加入过程中,达到的最高温度为-65.6℃。完成B(OMe)3的添加后,反应混合物回温至室温过夜。一旦反应混合物达到室温,在该温度(~-20.4℃)下让反应混合物在搅拌1小时。为了反应和稳定性研究,去除PBA-diMe溶液(115.74g)。用内标物(苯戊酮)通过GC法对PBA-diMe分析,得到17.07%重量的PBE(13.02%重量的PBA)。这个过程获得95%的PBA回收。一些PBA-diMe溶液用于Suzuki的偶合反应中。向配有冷凝器、热电偶温度探针、磁搅拌棒和N2入口的50ml三颈圆底烧瓶中加入AcAP-Me(3.0g,11.4mmol)。向圆底烧瓶中加入PPh3(90mg,0.342mmol),接着加入TBAB(37mg,0.114mmol)。在氮气氛下将固体Pd(OAc)2(26mg,0.114mmol)加入到圆底烧瓶中。边搅拌边用N2对MeCN(19.0mL)单独吹扫30分钟,然后加入到反应混合物中。边搅拌边用N2对PBA-diMe溶液(17.07wt%,14.82mol)吹扫30分钟,然后加入到反应混合物中。搅拌反应混合物5分钟,然后加入K2CO3水溶液(22.8%,17mL,预先用N2喷雾30分钟)。加热反应混合物至65℃,并搅拌2小时。2小时后,由GC法对反应物取样,确定反应的完成。GC显示产物很少(<5%)。GC还显示AcAP-Me完全耗光(可能是由于水解)。
尽管本发明可允许各种变形和替代形式,这里借助于实施例来详细描述了特定实施方式。然而,可以理解的是,本发明无意受限于所公开的特定形式。相反,本发明涵盖了由下面所附权利要求和其合法等同物所界定的本发明范围内的所有改进物,等同物和替代物。
Claims (14)
1.一种分离4-氯-2-氟-3-取代的-苯基硼酸酯的方法,包括:
将二氧化碳气体或二氧化碳固体(干冰)加入到包含4-氯-2-氟-3-取代的-苯基硼酸酯,惰性有机溶剂和至少一种锂盐的溶液中,以使所述至少一种锂盐与二氧化碳气体反应,形成包含所述4-氯-2-氟-3-取代的-苯基硼酸酯、所述惰性有机溶剂和沉淀固体的混合物;和从混合物中除去沉淀固体。
2.权利要求1所述的方法,其中将二氧化碳气体或二氧化碳固体(干冰)加入到包含4-氯-2-氟-3-取代的-苯基硼酸酯,惰性有机溶剂和至少一种锂盐的溶液中包括使二氧化碳气体鼓泡通过温度范围为20℃至25℃的所述溶液。
3.权利要求1所述的方法,其中将二氧化碳气体或二氧化碳固体(干冰)加入到包含4-氯-2-氟-3-取代的-苯基硼酸酯,惰性有机溶剂和至少一种锂盐的溶液中包括将二氧化碳气体加入到包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷和至少一种锂盐的溶液中。
4.权利要求3所述的方法,其中从所述混合物中除去沉淀固体包括回收1,2-二甲氧基乙烷中的4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯。
5.权利要求4所述的方法,其中回收1,2-二甲氧基乙烷中的4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯包括获得收率大于或等于90%的4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯。
6.合成和分离4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯的方法,包括
用n-丁基锂接触包含2-氯-6-氟苯甲醚和1,2-二甲氧基乙烷的溶液,形成包含6-氯-2-氟-3-锂苯甲醚和1,2-二甲氧基乙烷的反应混合物;
用硼酸三甲酯接触所述反应混合物形成包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷和至少一种锂盐的盐化苯基硼酸酯溶液;
将二氧化碳气体或二氧化碳固体(干冰)引入到所述盐化苯基硼酸酯溶液中,形成包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷和甲基碳酸锂的混合物;和
分离甲基碳酸锂以形成包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯和1,2-二甲氧基乙烷的脱盐苯基硼酸酯溶液。
7.权利要求6所述的方法,其中将二氧化碳气体或二氧化碳固体(干冰)引入到所述盐化苯基硼酸酯溶液中形成包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷和甲基碳酸锂的混合物包括使二氧化碳气体鼓泡通过温度范围为20℃至25℃的盐化苯基硼酸酯溶液。
8.权利要求6所述的方法,其中分离甲基碳酸锂以形成包含4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯,1,2-二甲氧基乙烷和甲基碳酸锂的脱盐苯基硼酸酯溶液包括获得收率高于或等于90%的4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯。
9.权利要求8所述的方法,还包括使用所述脱盐苯基硼酸酯溶液而无需浓缩或干燥。
10.权利要求1所述的方法,其进一步包括将4-氯-2-氟-3-取代的-苯基硼酸酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应以制备甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯。
11.权利要求10所述的方法,其中将4-氯-2-氟-3-取代的-苯基硼酸酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应包括在钯催化剂,配位体,碱和溶剂的存在下,将4-氯-2-氟-3-取代的-苯基硼酸酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应,所述溶剂包括4-甲基戊烷-2-酮,乙腈,甲苯,乙酸乙酯和水中的至少一种。
12.权利要求10所述的方法,其中将4-氯-2-氟-3-取代的-苯基硼酸酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应以制备甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯包括将4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应以制备甲基4-乙酰氨基-3-氯-6-(4-氯-2-氟-甲氧基苯基)吡啶-2-羧酸酯。
13.权利要求12所述的方法,其中将4-氯-2-氟-3-甲氧基苯基硼酸二甲基酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应以制备甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-甲氧基苯基)吡啶-2-羧酸酯包括获得收率大于或等于85%的甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-甲氧基苯基)吡啶-2-羧酸酯。
14.权利要求10所述的方法,其中将4-氯-2-氟-3-取代的-苯基硼酸酯与甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯反应以制备甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯包括:
将钯催化剂,配位体和碱加入到包含(4-氯-2-氟-3-取代的-苯基)硼酸酯,甲基4-乙酰氨基-3,6-二氯吡啶-2-羧酸酯和至少一种溶剂的去氧混合物中以形成偶合反应混合物;
在40℃至70℃范围的温度下搅拌所述偶合反应混合物以形成包含水相和有机相的多相溶液,所述有机相包括甲基-4-乙酰氨基-3-氯-6-(4-氯-2-氟-3-取代的-苯基)吡啶-2-羧酸酯;和分离有机相和水相。
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CN110558321A (zh) * | 2012-12-21 | 2019-12-13 | 美国陶氏益农公司 | 除草组合物 |
CA2923058A1 (en) | 2013-09-05 | 2015-03-12 | Dow Agrosciences Llc | Methods for producing borylated arenes |
TW201625354A (zh) | 2014-06-16 | 2016-07-16 | 陶氏農業科學公司 | 用於製備氧硼基化芳烴之方法 |
MX2018014174A (es) * | 2016-05-19 | 2019-03-14 | Dow Agrosciences Llc | Sintesis de 6-aril-4-aminopicolinatos y 2-aril-6-aminopirimidin-4- carboxilatos mediante acoplamiento suzuki directo. |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101360719A (zh) * | 2006-01-13 | 2009-02-04 | 美国陶氏益农公司 | 2-(多取代芳基)-6-氨基-5-卤代-4-嘧啶甲酸及其作为除草剂的用途 |
WO2009029735A1 (en) * | 2007-08-30 | 2009-03-05 | Dow Agrosciences Llc | 2-(substituted phenyl)-6-amino-5-alkoxy, thioalkoxy and aminoalkyl-4-pyrimidinecarboxylates and their use as herbicides |
CN101778829A (zh) * | 2007-08-13 | 2010-07-14 | 陶氏益农公司 | 2-(2-氟-取代的苯基)-6-氨基-5-氯-4-嘧啶羧酸衍生物及其作为除草剂的用途 |
CN101970446A (zh) * | 2008-01-11 | 2011-02-09 | 陶氏益农公司 | 对1-氟-2-取代的-3-氯苯选择性脱质子化和官能化的方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR037228A1 (es) * | 2001-07-30 | 2004-11-03 | Dow Agrosciences Llc | Compuestos del acido 6-(aril o heteroaril)-4-aminopicolinico, composicion herbicida que los comprende y metodo para controlar vegetacion no deseada |
DE10150615A1 (de) * | 2001-10-12 | 2003-04-30 | Clariant Gmbh | Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte |
BR122015016965B8 (pt) * | 2006-01-13 | 2022-06-28 | Dow Agrosciences Llc | 6-(aril polissubstituído)-4-aminopicolinatos, composição herbicida, e método para controle de vegetação indesejável |
US7964758B2 (en) * | 2006-02-13 | 2011-06-21 | Nissan Chemical Industries, Ltd. | Process for production of 2-(substituted phenyl)-3,3,3-trifluoropropene compound |
AU2008308815B2 (en) * | 2007-10-02 | 2012-02-02 | Corteva Agriscience Llc | 2-substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecarboxylic acids and 6-substituted-4-amino-3- alkyl, alkenyl or alkynyl picolinic acids and their use as herbicides |
PT2725903T (pt) * | 2011-06-30 | 2020-06-30 | Dow Agrosciences Llc | 3-alcoxi-, tioalquil- e amino-4-aminopicolinatos 6-substituídos e sua utilização como herbicidas |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101360719A (zh) * | 2006-01-13 | 2009-02-04 | 美国陶氏益农公司 | 2-(多取代芳基)-6-氨基-5-卤代-4-嘧啶甲酸及其作为除草剂的用途 |
CN101778829A (zh) * | 2007-08-13 | 2010-07-14 | 陶氏益农公司 | 2-(2-氟-取代的苯基)-6-氨基-5-氯-4-嘧啶羧酸衍生物及其作为除草剂的用途 |
WO2009029735A1 (en) * | 2007-08-30 | 2009-03-05 | Dow Agrosciences Llc | 2-(substituted phenyl)-6-amino-5-alkoxy, thioalkoxy and aminoalkyl-4-pyrimidinecarboxylates and their use as herbicides |
CN101970446A (zh) * | 2008-01-11 | 2011-02-09 | 陶氏益农公司 | 对1-氟-2-取代的-3-氯苯选择性脱质子化和官能化的方法 |
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