CN108863845B - Preparation method of trifloxystrobin and intermediate thereof - Google Patents
Preparation method of trifloxystrobin and intermediate thereof Download PDFInfo
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- CN108863845B CN108863845B CN201810951923.3A CN201810951923A CN108863845B CN 108863845 B CN108863845 B CN 108863845B CN 201810951923 A CN201810951923 A CN 201810951923A CN 108863845 B CN108863845 B CN 108863845B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000005857 Trifloxystrobin Substances 0.000 title claims description 26
- ONCZDRURRATYFI-TVJDWZFNSA-N trifloxystrobin Chemical compound CO\N=C(\C(=O)OC)C1=CC=CC=C1CO\N=C(/C)C1=CC=CC(C(F)(F)F)=C1 ONCZDRURRATYFI-TVJDWZFNSA-N 0.000 title claims description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000005893 bromination reaction Methods 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- WMGVPDQNPUQRND-UHFFFAOYSA-N (2-methylphenyl)acetonitrile Chemical compound CC1=CC=CC=C1CC#N WMGVPDQNPUQRND-UHFFFAOYSA-N 0.000 claims description 5
- UMASJAGFFWQJGQ-UHFFFAOYSA-N 2-hydroxyimino-2-(2-methylphenyl)acetonitrile Chemical compound CC1=CC=CC=C1C(=NO)C#N UMASJAGFFWQJGQ-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- PSOUEYMPCQDWAH-UHFFFAOYSA-N n-methoxy-2-methylbenzenecarboximidoyl cyanide Chemical compound CON=C(C#N)C1=CC=CC=C1C PSOUEYMPCQDWAH-UHFFFAOYSA-N 0.000 claims description 5
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical group CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- LDPXOYHMGOQPIV-JLHYYAGUSA-N methyl (2e)-2-[2-(bromomethyl)phenyl]-2-methoxyiminoacetate Chemical compound CO\N=C(\C(=O)OC)C1=CC=CC=C1CBr LDPXOYHMGOQPIV-JLHYYAGUSA-N 0.000 claims description 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- YCINJZQUXAFTQD-UHFFFAOYSA-N methyl 2-methoxyimino-2-(2-methylphenyl)acetate Chemical compound CON=C(C(=O)OC)C1=CC=CC=C1C YCINJZQUXAFTQD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims 2
- IDUHIHLGRMMRJW-UHFFFAOYSA-N 2-methoxyimino-2-(2-methylphenyl)acetamide Chemical compound CON=C(C(N)=O)C1=CC=CC=C1C IDUHIHLGRMMRJW-UHFFFAOYSA-N 0.000 claims 1
- 239000005869 Pyraclostrobin Substances 0.000 claims 1
- 238000003810 ethyl acetate extraction Methods 0.000 claims 1
- YCINJZQUXAFTQD-ZRDIBKRKSA-N methyl (2e)-2-methoxyimino-2-(2-methylphenyl)acetate Chemical compound CO\N=C(\C(=O)OC)C1=CC=CC=C1C YCINJZQUXAFTQD-ZRDIBKRKSA-N 0.000 claims 1
- HZRSNVGNWUDEFX-UHFFFAOYSA-N pyraclostrobin Chemical compound COC(=O)N(OC)C1=CC=CC=C1COC1=NN(C=2C=CC(Cl)=CC=2)C=C1 HZRSNVGNWUDEFX-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 description 22
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000006146 oximation reaction Methods 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 12
- -1 o-methoxyaminophenylacetic acid methyl ester Chemical compound 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- QQGVWMIRCZEUBB-UHFFFAOYSA-N n-[1-[3-(trifluoromethyl)phenyl]ethylidene]hydroxylamine Chemical compound ON=C(C)C1=CC=CC(C(F)(F)F)=C1 QQGVWMIRCZEUBB-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 230000032050 esterification Effects 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 230000031709 bromination Effects 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 4
- 238000006266 etherification reaction Methods 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000012286 potassium permanganate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- RZWGTXHSYZGXKF-UHFFFAOYSA-N 2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1CC(O)=O RZWGTXHSYZGXKF-UHFFFAOYSA-N 0.000 description 3
- 238000007333 cyanation reaction Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- LDPXOYHMGOQPIV-UHFFFAOYSA-N methyl 2-[2-(bromomethyl)phenyl]-2-methoxyiminoacetate Chemical compound CON=C(C(=O)OC)C1=CC=CC=C1CBr LDPXOYHMGOQPIV-UHFFFAOYSA-N 0.000 description 3
- GMZGDMPLWXWBQJ-UHFFFAOYSA-N methyl 2-[2-(chloromethyl)phenyl]-2-methoxyiminoacetate Chemical compound CON=C(C(=O)OC)C1=CC=CC=C1CCl GMZGDMPLWXWBQJ-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 3
- 229940049953 phenylacetate Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- YXWWHNCQZBVZPV-UHFFFAOYSA-N 2'-methylacetophenone Chemical compound CC(=O)C1=CC=CC=C1C YXWWHNCQZBVZPV-UHFFFAOYSA-N 0.000 description 2
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SDXVBCPFIYBOLF-UHFFFAOYSA-N [2-(bromomethyl)phenoxy]boronic acid Chemical compound OB(O)OC1=CC=CC=C1CBr SDXVBCPFIYBOLF-UHFFFAOYSA-N 0.000 description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BRAHRRYCGOLXPW-UHFFFAOYSA-N methyl 2-[2-(bromomethyl)phenyl]acetate Chemical compound COC(=O)CC1=CC=CC=C1CBr BRAHRRYCGOLXPW-UHFFFAOYSA-N 0.000 description 2
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000012414 tert-butyl nitrite Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- PSOUEYMPCQDWAH-BENRWUELSA-N (1e)-n-methoxy-2-methylbenzenecarboximidoyl cyanide Chemical compound CO\N=C(\C#N)C1=CC=CC=C1C PSOUEYMPCQDWAH-BENRWUELSA-N 0.000 description 1
- PSOUEYMPCQDWAH-ZRDIBKRKSA-N (1z)-n-methoxy-2-methylbenzenecarboximidoyl cyanide Chemical compound CO\N=C(/C#N)C1=CC=CC=C1C PSOUEYMPCQDWAH-ZRDIBKRKSA-N 0.000 description 1
- UMASJAGFFWQJGQ-LUAWRHEFSA-N (2e)-2-hydroxyimino-2-(2-methylphenyl)acetonitrile Chemical compound CC1=CC=CC=C1\C(=N/O)C#N UMASJAGFFWQJGQ-LUAWRHEFSA-N 0.000 description 1
- VQRBXYBBGHOGFT-UHFFFAOYSA-N 1-(chloromethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CCl VQRBXYBBGHOGFT-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- TXZFBHYDQGYOIT-UHFFFAOYSA-N 2-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=CC=C1C(Cl)=O TXZFBHYDQGYOIT-UHFFFAOYSA-N 0.000 description 1
- MVJIUTPZBDDMPF-UHFFFAOYSA-N 2-(chloromethyl)benzoyl cyanide Chemical compound ClCC1=CC=CC=C1C(=O)C#N MVJIUTPZBDDMPF-UHFFFAOYSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 1
- HKXFUXDJANRWMC-BWAHOGKJSA-N COC(\C(\C1=C(C=CC=C1)CONC(C)C1=CC(=CC=C1)C(F)(F)F)=N/OC)=O Chemical compound COC(\C(\C1=C(C=CC=C1)CONC(C)C1=CC(=CC=C1)C(F)(F)F)=N/OC)=O HKXFUXDJANRWMC-BWAHOGKJSA-N 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 244000141359 Malus pumila Species 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 241000233679 Peronosporaceae Species 0.000 description 1
- 241000918585 Pythium aphanidermatum Species 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 229930182692 Strobilurin Natural products 0.000 description 1
- 244000273928 Zingiber officinale Species 0.000 description 1
- 235000006886 Zingiber officinale Nutrition 0.000 description 1
- MYVJCOQGXCONPE-UHFFFAOYSA-N [2-(bromomethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=CC=C1CBr MYVJCOQGXCONPE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- OPHUWKNKFYBPDR-UHFFFAOYSA-N copper lithium Chemical compound [Li].[Cu] OPHUWKNKFYBPDR-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000008397 ginger Nutrition 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BLEMRRXGTKTJGT-UHFFFAOYSA-N methyl 2-(2-methylphenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1C BLEMRRXGTKTJGT-UHFFFAOYSA-N 0.000 description 1
- KLADGFFMZICZTG-UHFFFAOYSA-N methyl 2-chloro-2-methoxyiminoacetate Chemical compound CON=C(Cl)C(=O)OC KLADGFFMZICZTG-UHFFFAOYSA-N 0.000 description 1
- 230000006540 mitochondrial respiration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种肟菌酯的制备方法；肟菌酯的制备反应如下：R选自：C2～C5直链烷基或C3～C5支链烷基；溴化反应中，溴化剂选择NBS或1,3‑二溴‑5,5‑二甲基海因。The invention relates to a preparation method of tristrobin; the preparation reaction of tristrobin is as follows: 
R is selected from: C 2 -C 5 straight-chain alkyl or C 3 -C 5 branched-chain alkyl; in the bromination reaction, the brominating agent is selected from NBS or 1,3-dibromo-5,5-dimethyl sea because.
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of trifloxystrobin and an intermediate 2-methyl-alpha-methoxyimino phenylacetamide thereof.
Background
Trifloxystrobin (trifloxystrobin, trade name Flint) chemical name: (2Z) -2-methoxyimino-2- [2- [ [1- [3- (trifluoromethyl) phenyl ] ethylamino ] oxymethyl ] phenyl ] acetic acid methyl ester:
the trifloxystrobin is a high-efficiency, safe and environment-friendly strobilurin fungicide, is used as a novel mitochondrial respiration inhibitor, has the characteristics of high efficiency, broad spectrum, low toxicity, environmental friendliness, unique action mechanism and the like, and is a hotspot of fungicide research at present. The compound bactericide is mainly used for stem and leaf treatment, has special effects on powdery mildew and leaf spot, and also has good activity on rust disease, downy mildew, damping off and apple scab.
Chinese patent No. [ CN 1049426C,2000] takes o-bromomethyl phenylacetate as a starting material, firstly generates etherification reaction with phenylglyoxylic acid, then generates o-methoxyaminophenylacetic acid methyl ester by reaction with methanol under an acidic condition, then performs oximation reaction with m-trifluoromethyl acetophenone, and prepares trifloxystrobin by oximation of tert-butyl nitrite and methylation of dimethyl sulfate, wherein the total yield is 40.5%:
the route has five steps, the reaction steps are reasonable, but the expensive o-bromomethyl phenylacetate is used in the reaction.
The world patent [ WO 9520569,1995] researches trifloxystrobin, namely, firstly carrying out etherification reaction on o-bromomethylphenyl boric acid and m-trifluoromethyl acetophenone oxime, and then carrying out condensation reaction on the o-bromomethylphenyl boric acid and 2-chloro-2-methoxy imine methyl acetate under the catalysis of palladium to generate the trifloxystrobin:
the synthetic route is short, but the price of the raw material o-bromomethylbenzeneboronic acid is high; the yield is low due to the harsh conditions for the synthesis of methyl 2-chloro-2-methoxyiminoacetate and the presence of isomerization.
U.S. Pat. No. [ US 5194662,1993] uses methyl o-methylphenylacetate as an initial raw material, and obtains methyl o-bromomethylphenylacetate through bromination reaction, then the methyl o-bromomethylphenylacetate is condensed with m-trifluoromethyl acetophenone oxime, and then the trifloxystrobin is obtained through oxidation and oximation reactions:
the third oxidation step of the route is difficult.
Nibepo et al CN 101941921,2011 and ginger billow et al organic chemistry 2014,34(4),774-782 take toluene or substituted toluene as raw material, under the catalysis of anhydrous aluminum trichloride, take Friedel-crafts acylation reaction with oxalyl chloride monomethyl ester, then oximation and chlorination are carried out, and finally condensation with m-trifluoromethyl acetophenone oxime is carried out to obtain trifloxystrobin, wherein the total yield is 50.2%:
the friedel-crafts acylation reaction in the route has lower selectivity, which leads to lower yield; the price of the oxalyl chloride monomethyl ester is higher.
Plum flame and the like [ university of china, 2005,39(1),54-56] take o-bromotoluene as a raw material, and react with oxalyl chloride monomethyl ester under the action of an organic copper lithium reagent to generate a coupling reaction to obtain o-methyl benzoyl methyl formate, and then the o-methyl benzoyl methyl formate reacts with methoxylamine hydrochloride to generate an intermediate oxime ester, and the intermediate oxime ester is obtained through bromination and oximation reactions to obtain trifloxystrobin, wherein the total yield is 25%:
the coupling reaction in the first step of the route is complex, the conditions are harsh, the number of byproducts is large, and the process has high requirements on equipment.
Chinese patents [ CN 1560027,2005; CN 1793115,2006] o-methylacetophenone is used as a raw material, oxidized by potassium permanganate under the alkalescent condition, esterified, oximated and brominated, and finally condensed with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin, wherein the total yield is 39%:
chenwei et al [ chemical research, 2014,25(1),16-19] use o-tolylacetic acid as raw material, firstly oxidize by potassium permanganate under alkaline condition, then carry out esterification, oximation and bromination reactions, finally generate trifloxystrobin by condensation reaction, and the total yield is 17%:
in the potassium permanganate oxidation method, the reaction process is difficult to control by using potassium permanganate as an oxidant, and methyl can be oxidized.
World patents [ WO 2013144924, US 5221762,1993], Chen-Can and so on [ fine chemical intermediates, 2004,34(5),25-26] and Ron and so on [ fine chemical intermediates, 2016,46(2),19-21] use o-methylbenzoic acid as raw material, and reflux with thionyl chloride to obtain o-methylbenzoyl chloride; then carrying out cyanation, esterification, oximation and bromination on the obtained intermediate, and etherifying the intermediate with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin, wherein the total yield is 16.2%:
the raw materials of the route are cheap and the operation is simple, but the second step reaction uses sodium cyanide with high toxicity.
Deluxe et al [ pesticide 2011,50(3),187-191] and chinese patent [ CN 101139308,2008] use o-hydroxymethyl benzoic acid lactone as a raw material, generate o-chloromethyl benzoyl chloride through ring opening, react with sodium cyanide as a cyanogen source to prepare o-chloromethyl benzoyl cyanide, and finally etherify the intermediate obtained through esterification and oximation with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin with a total yield of 22%:
according to the method, phthalide is used for ring opening to generate acyl chloride and chloromethyl, and the reaction conditions in each step are mild; but the second reaction step uses sodium cyanide, which is highly toxic.
Chinese patent [ CN 103524378,2015] takes o-tolylacetic acid as a raw material, and synthesizes trifloxystrobin through cyclization, oxidation, hydrolysis, oximation, chlorination and etherification, wherein the yield is 50.6%:
the raw materials of the route are cheap and easy to obtain, and the yield is high. But the oxidation process uses the expensive oxidant CAT 9901.
According to Chinese patent [ CN 105294490,2016] and world patent [ WO 2010089267], an o-hydroxymethylphenylacetic acid lactone method is used as a raw material, trifloxystrobin is obtained through 4 steps of reaction, and the total yield is 25%:
the price of o-hydroxymethylphenylacetic acid lactone used as a raw material in the route is high, and the first-step oximation reaction needs anhydrous and anaerobic operation.
Firewood and the like [ pesticide 2013,52(4), 258-:
the diazotization reaction condition adopted by the route is harsher, and more byproducts are generated.
Plum red [ the master thesis of the university of Hebei science and technology, 2015] takes o-methyl phenylacetonitrile as a raw material, and is subjected to oximation, methylation, hydrolysis, bromination and etherification to synthesize trifloxystrobin, wherein the yield is 30.8%:
the raw materials of the route are cheap and easy to obtain, and the reaction conditions are relatively mild. However, concentrated sulfuric acid is used in the esterification process, so that the equipment is highly corrosive.
The method is characterized in that the method takes o-methylbenzyl chloride as a starting material, and obtains a key intermediate 2-bromomethyl-alpha-methoxyimino phenylacetic acid methyl ester of trifloxystrobin through cyanation, oximation, methylation, esterification and bromination, wherein the yield is 41.6%.
The route is relatively mild, but uses highly toxic sodium cyanide.
U.S. Pat. No. 3, 5145980,1992 discloses a process for preparing 2-bromomethyl-alpha-methoxyimino methyl phenylacetate by reacting o-methylbenzaldehyde as a raw material with methoxyamine hydrochloride after cyanation and oxidation and then brominating, with a total yield of 16%:
the route is long, the total yield is low, and the first step reaction uses potassium cyanide with high toxicity.
Weixinghui et al [ Zhejiang chemical engineering, 2013,44(2),7-9] use o-methylphenylacetic acid as raw material, and synthesize 2-bromomethyl-alpha-methoxyimino phenylacetic acid methyl ester through esterification, oximation, methylation and bromination, with a total yield of 32%:
the reaction condition of the route is mild, and the method is a better method for preparing 2-bromomethyl-alpha-methoxyimino phenylacetic acid methyl ester.
Chinese patent [ CN 101711232,2010] uses o-chlorobenzyl chloride as raw material, uses morpholine to protect methylene, and then obtains 2-chloromethyl-alpha-methoxyimino phenylacetic acid methyl ester through 4 steps of Grignard reaction, esterification and oximation, the total yield is 22%:
the second step of the process is difficult to control, and the yield is 30.3%.
The world patent [ WO 9714688,1997] takes o-tolylacetonitrile as a raw material, and 2-chloromethyl-alpha-methoxyimino phenylacetic acid methyl ester is obtained through 5 steps of reaction, wherein the total yield is 23%:
the third reaction step of the route requires anhydrous and oxygen-free operation.
U.S. Pat. No. 4, 5756811,1998 discloses a method for preparing trifloxystrobin intermediate 2-chloromethyl- α -methoxyimino phenylacetic acid methyl ester by 3-step reaction using N, N-dimethylbenzylamine and dimethyl oxalate as raw materials, wherein the total yield is 55%:
the method has the advantages of relatively simple route and high yield, but n-butyllithium is required for the first step of reaction, and the reaction conditions are harsh.
In conclusion, the existing technology for preparing trifloxystrobin has the defects of difficult raw material source, high price, long synthesis route, harsh reaction conditions, difficult process control, high requirement on production equipment, high safety and environmental protection pressure, low yield and the like.
Disclosure of Invention
The invention aims to provide a preparation method of 2-methyl-alpha-methoxyimino phenylacetamide shown in a chemical structural formula I; the method is characterized by comprising the following preparation reactions:
r is selected from: c2～C5Straight chain alkyl or C3～C5A branched alkyl group.
The invention aims to provide a preparation method of 2-methyl-alpha-methoxyimino phenylacetamide, which comprises the following steps: the preparation method is characterized by comprising the following preparation operation processes:
stirring and dissolving 12mmol of sodium hydroxide and 10mL of methanol at 40 ℃, adding 5mmol of o-tolylacetonitrile, adding 7.5mmol of tert-butyl nitrite, heating to 60 ℃, and reacting for 1 h. The 2-methyl-alpha-hydroxyimino phenylacetonitrile is obtained by post-treatment with the yield of 100 percent.
Stirring 4mmol of 2-methyl-alpha-hydroxyiminophenylacetonitrile, 15mL of acetonitrile and 8mmol of KOH or NaOH at the temperature of 35-40 ℃ for 0.5h, cooling, slowly dropwise adding 4.8mmol of dimethyl sulfate at the temperature of below 10 ℃, stirring at the temperature of 35 ℃ for 3h, and performing aftertreatment to obtain 0.626g of light yellow oily liquid with the yield of 90%.
Adding 5mmol of 20% potassium hydroxide solution into 5mmol of 2-methyl-alpha-methoxyimino phenylacetonitrile and 5mL of ethanol, reacting for 3h at 60 ℃, and performing post-treatment to obtain 0.900g of (E) -2-methyl-alpha-methoxyimino phenylacetamide with single configuration, wherein the yield is 92.5% and the melting point is 123-125 ℃.
The invention also provides a method for preparing trifloxystrobin from 2-methyl-alpha-methoxyimino phenylacetamide shown in a chemical structural formula I; the method is characterized by comprising the following preparation reactions:
r is selected from: c2～C5Straight chain alkyl or C3～C5A branched alkyl group; in the bromination reaction, NBS or 1, 3-dibromo-5, 5-dimethylhydantoin is selected as a brominating agent.
Compared with the prior art, the method has the advantages of mild reaction conditions, cheap and easily-obtained raw materials, simple and convenient post-treatment and high total yield (43.5%). The invention adopts the key intermediate of 2-methyl-alpha-methoxyimino phenylacetamide to prepare the trifloxystrobin for the first time.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 2-methyl-alpha-hydroxyiminophenylacetonitrile
0.480g (12mmol) of sodium hydroxide and 10mL of methanol are dissolved by stirring at 40 ℃, 0.655g (5mmol) of o-tolylacetonitrile is added, and 0.773g (7.5mmol) of nitroso is addedAnd (4) tert-butyl ester, heating to 60 ℃, monitoring by TLC, and reacting for 1 h. And (3) carrying out desolventizing under reduced pressure to recover methanol, adding 20mL of water, adjusting the pH value to be neutral by hydrochloric acid, extracting by ethyl acetate, drying by anhydrous sodium sulfate, carrying out desolventizing to recover the ethyl acetate, wherein the yield is 100%, and directly using the ethyl acetate in the next step. (E) -2-methyl- α -hydroxyiminophenylacetonitrile:1H NMR(400MHz，CDCl3)：13.78(s，1H，OH)，7.53～7.32(m，4H，C6H4)，2.44(s，3H，CH3) (Z) -2-methyl- α -hydroxyiminophenylacetonitrile:1H NMR(400MHz，CDCl3)：13.78(s，1H，OH)，7.46～7.33(m，4H，C6H4)，2.25(s，3H，CH3)。
example 2
Preparation of 2-methyl-alpha-methoxyimino phenylacetonitrile
0.640g (4mmol) of 2-methyl-alpha-hydroxyiminophenylacetonitrile, 15mL of acetonitrile, 0.448g (8mmol) of powdered KOH, stirring at 35-40 ℃ for 0.5h, cooling, slowly adding dropwise 0.605g (4.8mmol) of dimethyl sulfate below 10 ℃, stirring at 35 ℃ for 3h, and monitoring by TLC. Standing, performing suction filtration, and performing rotary evaporation to recover acetonitrile. The residue was dissolved in ethyl acetate, neutralized with dilute hydrochloric acid, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, desolventized, and separated by column chromatography (PE: EA ═ 8:1) to give 0.626g of 2-methyl- α -methoxyiminophenylacetonitrile in a yield of 90%. (E) -2-methyl- α -methoxyiminophenylacetonitrile:1H NMR(400MHz，CDCl3)：7.56～7.25(m，4H，C6H4)，4.20(s，3H，NOCH3)，2.51(s，3H，CH3) (ii) a (Z) -2-methyl- α -methoxyiminophenylacetonitrile:1H NMR(400MHz，CDCl3)：7.38～7.25(m，4H，C6H4)，4.06(s，3H，NOCH3)，2.31(s，3H，CH3)。
example 3
Preparation of 2-methyl-alpha-methoxyimino phenylacetamide
0.870g (5mmol) of 2-methyl-. alpha. -methoxyiminophenylacetonitrile and 5mL of ethanol were added with 1.400g (5mmol) of 20% potassium hydroxide or NaOH solution, and reacted at 60 ℃ for 3 hours, followed by TLC. The solvent was recovered by rotary evaporation, the residue was poured into 20mL of ice water, and the solid precipitated, filtered off with suction and washed with water. Drying the filter cake, extracting the filtrate with ethyl acetate, drying with anhydrous sodium sulfate, desolventizing and drying to obtain 0.900g of 2-methyl-alpha-methoxyimino phenylacetamide, wherein the yield is 92.5 percent and the melting point is 123-125 ℃.1H NMR(400MHz，DMSO-d6)：7.97(s，1H，NH2)，7.73(s，1H，NH2)，7.40～7.22(m，4H，C6H4)，3.89(s，3H，NOCH3)，2.42(s，3H，CH3)。
Example 4
Preparation of 2-methyl-alpha-methoxyimino methyl phenylacetate
0.960g (5mmol) of 2-methyl-alpha-methoxyimino phenylacetamide and methanol, introducing hydrogen chloride gas, stirring for 12h at 60 ℃, monitoring by TLC, desolventizing under reduced pressure, adding 20mL of water, extracting with ethyl acetate, washing with saturated sodium bicarbonate, washing with water, drying with anhydrous sodium sulfate, desolventizing under reduced pressure, and drying to obtain 2-methyl-alpha-methoxyimino phenylacetic acid methyl ester, wherein the yield is 90.5%, and the melting point is 69-71 ℃.1H NMR(400MHz，DMSO-d6)：7.34～7.09(m，4H，C6H4)，3.94(s，3H，NOCH3)，3.76(s，3H，OCH3)，2.09(s，3H，CH3)。
Example 5
(E) Preparation of (E) -2-bromomethyl-alpha-methoxyiminophenylacetic acid methyl ester
0.414g (2.00mmol) of methyl (E) -2-methyl-. alpha. -methoxyimino-phenylacetate, 5mL of dichloroethane, 0.300g (1.05mmol) of 1, 3-dibromo-5, 5-dimethylhydantoin (abbreviated as dibromohydantoin), 0.100g (0.61mmol) of AIBN, reaction at 82 ℃ for 5.0h, monitoring by TLC and desolventizing. Adding 5mL of water, extracting with ethyl acetate, washing with sodium hydroxide solution, drying with anhydrous sodium sulfate, desolventizing, and separating by column chromatography (PE: EA is 20:1) to obtain 0.472g of (E) -2-bromomethyl-alpha-methoxyimino phenylacetic acid methyl ester with the yield of 82.5%.1H NMR(400MHz，CDCl3)：7.52～7.35，7.17～7.12(m，4H，C6H4)，4.34(s，2H，CH2)，4.07(s，3H，NOCH3)，3.88(s，3H，OCH3)。
Example 6
Preparation of m-trifluoromethyl acetophenone oxime
1.000g (5.0mmol) of m-trifluoromethyl acetophenone, 0.5g (7.0mmol) of hydroxylamine hydrochloride and 10mL of ethanol are added, 0.350g (8.8mmol) of sodium hydroxide is added to adjust the pH value to 8.0, the mixture is refluxed for 1.0h, poured into ice water, adjusted to the pH value of 2.0 by hydrochloric acid, a large amount of white solid is separated out, and the white solid is filtered, washed and dried to obtain 0.965g of white solid m-trifluoromethyl acetophenone oxime with the yield of 95.5 percent.1H NMR(400MHz，CDCl3)：7.92～7.48(m，4H，C6H4)，2.32(s，3H，CH3)。
Example 7
Preparation of trifloxystrobin
0.25g (1.22mmol) of m-trifluoromethylacetophenone, 4ml of DMF, 0.133g (2.46mmol) of sodium methoxide are stirred at room temperature for 15min, cooled to 5 ℃, added with 0.422g (1.47mmol) of (E) -2-bromomethyl-alpha-methoxyimino phenylacetic acid methyl ester, reacted at room temperature for 5h, poured into ice water, extracted by ethyl acetate, washed by dilute hydrochloric acid, washed by water and separated by column chromatography (PE: EA is 20:1) to obtain 0.375g of m-trifluoromethylacetophenoneTrifloxystrobin, yield 70%.1H NMR(400MHz，CDCl3)：7.90～7.15(m，8H，2×C6H4)，5.15(s，2H，CH2)，4.03(s，3H，NOCH3)，3.82(s，3H，OCH3)，2.22(s，3H，CH3)；13C NMR(100 MHz，CDCl3)：163.34，153.66，149.58，137.23，135.99，129.84，129.42，129.28，128.83，128.80，128.56，127.79，125.65，125.61，122.91，122.87，74.94，63.81，52.90，12.54。
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| CN118405990B (en) * | 2024-07-02 | 2024-09-13 | 辽宁众辉生物科技有限公司 | Synthesis method of 2-methyl-alpha-hydroxy iminobenzyl cyanide |
| CN118724751A (en) * | 2024-07-16 | 2024-10-01 | 辽宁众辉生物科技有限公司 | A method for efficiently synthesizing a key intermediate of trifloxystrobin using a microchannel reactor |
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