KR100311196B1 - Fluropropenyl-substituted propenoic ester and amide compound having oxime bridge, process for preparing same and antifungal composition comprising same - Google Patents
Fluropropenyl-substituted propenoic ester and amide compound having oxime bridge, process for preparing same and antifungal composition comprising same Download PDFInfo
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- KR100311196B1 KR100311196B1 KR1019990033724A KR19990033724A KR100311196B1 KR 100311196 B1 KR100311196 B1 KR 100311196B1 KR 1019990033724 A KR1019990033724 A KR 1019990033724A KR 19990033724 A KR19990033724 A KR 19990033724A KR 100311196 B1 KR100311196 B1 KR 100311196B1
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- South Korea
- Prior art keywords
- formula
- compound
- methyl
- substituted
- phenyl
- Prior art date
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- -1 amide compound Chemical class 0.000 title claims abstract description 66
- 150000002148 esters Chemical class 0.000 title claims abstract description 12
- 239000012871 anti-fungal composition Substances 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims abstract description 8
- 125000003544 oxime group Chemical group 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 61
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000000417 fungicide Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 230000000855 fungicidal effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 14
- 239000000126 substance Substances 0.000 abstract description 3
- 239000003899 bactericide agent Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 238000002360 preparation method Methods 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 33
- 239000002904 solvent Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 238000012360 testing method Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000003480 eluent Substances 0.000 description 13
- WRAQQYDMVSCOTE-UHFFFAOYSA-N phenyl prop-2-enoate Chemical compound C=CC(=O)OC1=CC=CC=C1 WRAQQYDMVSCOTE-UHFFFAOYSA-N 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 241000209094 Oryza Species 0.000 description 12
- 235000007164 Oryza sativa Nutrition 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 235000009566 rice Nutrition 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 125000001841 imino group Chemical group [H]N=* 0.000 description 9
- 230000003902 lesion Effects 0.000 description 9
- 229940049953 phenylacetate Drugs 0.000 description 9
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 241000209219 Hordeum Species 0.000 description 7
- 235000007340 Hordeum vulgare Nutrition 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 125000003944 tolyl group Chemical group 0.000 description 7
- 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 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 241000209140 Triticum Species 0.000 description 6
- 235000021307 Triticum Nutrition 0.000 description 6
- 239000008272 agar Substances 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- HNFKMXRKRBYZJN-UHFFFAOYSA-N 5-ethenyl-6,6-difluoro-5-(trifluoromethyl)cyclohexa-1,3-diene Chemical compound FC(F)(F)C1(C=C)C=CC=CC1(F)F HNFKMXRKRBYZJN-UHFFFAOYSA-N 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000011081 inoculation Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 4
- 240000008067 Cucumis sativus Species 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 3
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- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- JAICGBJIBWDEIZ-UHFFFAOYSA-N 3-phenylmethoxybenzaldehyde Chemical compound O=CC1=CC=CC(OCC=2C=CC=CC=2)=C1 JAICGBJIBWDEIZ-UHFFFAOYSA-N 0.000 description 3
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- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000227653 Lycopersicon Species 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 239000004480 active ingredient Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 3
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- 239000011777 magnesium Substances 0.000 description 3
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- BLEMRRXGTKTJGT-UHFFFAOYSA-N methyl 2-(2-methylphenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1C BLEMRRXGTKTJGT-UHFFFAOYSA-N 0.000 description 3
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
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- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- RIGZIGSLGOTINN-MSOZMUFPSA-N methyl (2e,3z,5e)-2-(methoxymethylidene)-3-methyl-6-[3-(3-methylbut-2-enoxy)phenyl]hexa-3,5-dienoate Chemical compound CO\C=C(\C(=O)OC)/C(/C)=C\C=C\C1=CC=CC(OCC=C(C)C)=C1 RIGZIGSLGOTINN-MSOZMUFPSA-N 0.000 description 1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
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- 229910052698 phosphorus Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C207/00—Compounds containing nitroso groups bound to a carbon skeleton
- C07C207/04—Compounds containing nitroso groups bound to a carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
- A01N33/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds only one oxygen atom attached to the nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
Abstract
본 발명은 살균 활성이 우수하고 항균 범위가 넓은, 하기 화학식 1로 표시되는, 옥심기를 가교로 하고 불소화 프로페닐기가 치환된 신규의 프로페노익 에스테르 및 아미드 화합물, 이의 제조 방법 및 이를 포함하는 살균제 조성물에 관한 것이다.The present invention provides a novel propenoic ester and amide compound having an oxime group crosslinked and substituted with a fluorinated propenyl group represented by the following Chemical Formula 1, which has excellent bactericidal activity and a broad antibacterial range, a method for preparing the same, and a bactericide composition comprising the same It is about.
상기 식에서, X는 CH 또는 N이고, Y는 O 또는 NH이며, R1은 수소, C1-4알킬 또는 할로겐으로 하나이상이 치환된 C1-4알킬이고, R2는 페닐 또는, C1-4알킬, 할로겐으로 치환된 C1-4알킬, C1-4알콕시, 메틸렌디옥시 또는 할로겐으로 하나이상이 치환된 페닐이다.And wherein, X is CH or N, Y is O or NH, R 1 is hydrogen, and one or more C 1-4 alkyl substituted with C 1-4 alkyl or halogen, R 2 is phenyl or, C 1 -4 alkyl, C 1-4 alkyl substituted by halogen, C 1-4 alkoxy, methylenedioxy or phenyl substituted one or more by halogen.
Description
본 발명은 살균 활성이 우수한, 옥심기를 가교로 하고 불소화 프로페닐기가 치환된 신규의 프로페노익 에스테르 및 아미드 화합물에 관한 것이다.The present invention relates to novel propenoic ester and amide compounds having an oxime group with excellent bactericidal activity and having a fluorinated propenyl group substituted.
최근 담자균류의 균사로부터 얻어진 스트로빌루린(strobilurin)A, B, C 및 오데만신(Oudemansin)A, B 등의 천연물이 고활성의 항균물질로서 보고된 이후 이들 화합물이 공통적으로 취하고 있는 베타-메톡시아크릴레이트(β-methoxyacrylate, MOA) 구조를 모핵으로 하여 새롭게 구조변환 된 프로페노익 에스테르 및 아미드계의 살균제 개발이 활발히 진행되고 있다.Recently, natural products such as strobilurin A, B, C, and Oudemansin A, B obtained from the mycelia of basidiomycete have been reported as highly active antimicrobial agents, and these compounds are commonly taken as beta-meth. The development of newly transformed propenoic ester and amide fungicides using methoxyacrylate (β-methoxyacrylate, MOA) as a mother nucleus has been actively conducted.
프로페노익 에스테르 및 아미드계 화합물들은 저약량으로 탁월한 살균활성을 나타낼 뿐만 아니라 침투이행성이 우수하며 항균범위가 넓다는 등 살균제로서의 장점을 갖추고 있다. 이와 같은 특징은 기존에 사용되고 있는 약제들이 지니고 있는약효가 약하거나 항균범위 등이 넓지 못하며, 약효의 지속성이 짧다는 등의 문제점을 개선할 수 있는 것으로 평가된다.Propenoic esters and amide-based compounds exhibit excellent sterilizing activity at low doses, as well as excellent penetration performance and broad antimicrobial range. Such characteristics are evaluated as being able to improve problems such as weak drug efficacy or antimicrobial range, and short duration of drugs, which are used in the existing drugs.
특히, 현재 사용되고 있는 살균제들은 우수한 살균효과에도 불구하고 같은 구조의 유사체가 지속적으로 개발, 사용되어 대상 균류들의 해당 농약에 대한 내성 발현이 문제화되고 있다.In particular, currently used fungicides, despite the excellent bactericidal effect, the same structure has been continuously developed and used, the expression of resistance to the pesticides of the target fungi problem.
이러한 문제점을 해결하기 위한 지속적인 노력의 일환으로 등장한 새로운 유형의 살균제인 프로페노익 에스테르 및 아미드계 화합물들은 예를 들면 제네카(Zeneca)사의 유럽 특허 제 A 0,278,595 호(1998), 노바티스(Novartis)사의 유럽 특허 제 0,782,982 A1 호(1996), 시바가이기(Ciba-Geigy)사의 WO 96/06072 호, 롱프랑(Rhone-Poulenc Agro)사의 WO 96/33164 A1 호, BASF사의 WO 9,856,774 호(1998), 독일 특허 제 724,200 호(1997), WO 9,906,379 호(1998), 독일 특허 제 732,846 호(1997), 아그레보UK (Agrevo UK)사의 WO 9,923,066 호(1998), 영국 특허 제 22,893 호(1997) 등에 공지되어 있다.New types of fungicides, propenoic esters and amide compounds, which emerge as part of an ongoing effort to solve this problem, are described, for example, in European Patent No. A 0,278,595 (1998) by Zeneca, Europe of Novartis Patent No. 0,782,982 A1 (1996), WO 96/06072 from Ciba-Geigy, WO 96/33164 A1 from Rhone-Poulenc Agro, WO 9,856,774 (1998) from BASF, Germany Patents 724,200 (1997), WO 9,906,379 (1998), German Patent 732,846 (1997), WO 9,923,066 (1998) by Agrevo UK, British Patent 22,893 (1997) and the like. have.
본 발명자들은 기존의 살균제 보다 살균 활성이 강력하고 독성이 낮으며 약효의 지속성이 개선된 경제성이 큰 화합물을 개발하기 위하여 불소화 프로페닐기가 치환된 신규의 프로페노익 에스테르 및 아미드계 화합물을 합성하고자 하였다.The present inventors have attempted to synthesize novel propenoic ester and amide compounds substituted with fluorinated propenyl groups in order to develop economical compounds having stronger bactericidal activity, lower toxicity, and improved drug sustainability than conventional fungicides. .
따라서, 본 발명의 목적은 살균 활성이 우수하고 항균 범위가 넓은, 옥심기를 가교로 하고 불소화 프로페닐기가 치환된 새로운 구조의 프로페노익 에스테르및 아미드 화합물을 제공하는 데 있다.Accordingly, an object of the present invention is to provide a propenoic ester and amide compound having a new structure having excellent sterilizing activity and a broad antibacterial range, having an oxime group as a crosslink and having a fluorinated propenyl group.
본 발명의 다른 목적은 상기 화합물의 제조 방법을 제공하는 데 있다.Another object of the present invention is to provide a method for preparing the compound.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 포함하는 살균제 조성물을 제공하는 것이다.Still another object of the present invention is to provide a fungicide composition comprising the compound as an active ingredient.
상기 목적에 따라, 본 발명에서는 하기 화학식 1로 표시되는, 옥심기를 가교로 하고 불소화 프로페닐기가 치환된 신규의 프로페노익 에스테르 및 아미드 화합물이 제공된다:According to the above object, the present invention provides a novel propenoic ester and amide compound having an oxime group crosslinked and substituted with a fluorinated propenyl group represented by Formula 1 below:
화학식 1Formula 1
상기 식에서, X는 CH 또는 N이고, Y는 O 또는 NH이며, R1은 수소, C1-4알킬 또는 할로겐으로 하나이상이 치환된 C1-4알킬이고, R2는 페닐 또는, C1-4알킬, 할로겐으로 치환된 C1-4알킬, C1-4알콕시, 메틸렌디옥시 또는 할로겐으로 하나이상이 치환된 페닐이다.And wherein, X is CH or N, Y is O or NH, R 1 is hydrogen, and one or more C 1-4 alkyl substituted with C 1-4 alkyl or halogen, R 2 is phenyl or, C 1 -4 alkyl, C 1-4 alkyl substituted by halogen, C 1-4 alkoxy, methylenedioxy or phenyl substituted one or more by halogen.
본 발명에 따른 화학식 1의 화합물은, 옥심기를 가교로 하며 불소화 프로페닐기가 도입된 새로운 구조를 갖는 신규 화합물이다.The compound of the formula (1) according to the present invention is a novel compound having a new structure in which an oxime group is crosslinked and a fluorinated propenyl group is introduced.
본 발명에 따른 화학식 1의 화합물 중에서 X가 N이고 Y가 NH이며 R1이 수소 또는 메틸기이고, R2가 페닐 또는, Cl 또는 F로 치환된 페닐인 경우가 바람직하다.Among the compounds of the formula (1) according to the invention, it is preferred if X is N, Y is NH, R 1 is hydrogen or methyl, and R 2 is phenyl or phenyl substituted with Cl or F.
본 발명의 화합물은 하기 반응식 1에 도시한 바와 같은 방법에 의해 제조할 수 있다.The compound of the present invention can be prepared by a method as shown in Scheme 1 below.
상기 식에서, X, Y, R1및 R2는 상기 정의한 바와 같다.Wherein X, Y, R 1 and R 2 are as defined above.
구체적으로, 본 발명에 따른 화학식 1의 화합물 중 Y가 O인 하기 화학식 1a의 프로페노익 에스테르 화합물은, 하기 화학식 2의 브롬화물을 하기 화학식 3의 옥심계 화합물과 염기 존재하에 반응시켜 하기 화학식 4의 화합물을 얻고 이를 팔라듐(Pd) 촉매 존재하에 수소화 반응시켜 탈벤질화(debenzylation)하여 하기 화학식 5a의 페놀성 에스테르계 화합물을 얻은 다음 이를 하기 화학식 6의 불소화 프로페닐계 화합물과 염기 존재하에 반응시킴으로써 고수율로 제조할 수 있다.Specifically, the propenoic ester compound of Formula 1a, in which Y is O, of the compound of Formula 1 according to the present invention is reacted with a bromide of Formula 2 with an oxime compound of Formula 3 in the presence of a base: Debenzylation was carried out by hydrogenation in the presence of a palladium (Pd) catalyst to obtain a phenolic ester compound of Formula 5a, and then reacted with a fluorinated propenyl compound of Formula 6 in the presence of a base. It can be produced in high yield.
상기 식에서, X, R1및 R2는 상기 정의한 바와 같다.Wherein X, R 1 and R 2 are as defined above.
본 발명에서 출발 물질로서 사용되는 화학식 2의 브롬화물은, X에 따라 하기 화학식 2a(X=CH) 및 2b(X=N)의 화합물을 포함한다.The bromide of formula (2) used as starting material in the present invention includes compounds of formulas (2a) (X = CH) and 2b (X = N), according to X.
화학식 2a로 표시되는 메틸 (2E)-3-메톡시-2-(2'-브로모메틸)페닐-2-프로페노에이트는 잘 알려진 공지된 방법에 의해 하기 반응식 2에 도시한 바와 같이 2-메틸페닐아세트산으로부터 에스테르화 및 포밀화, 메틸화, 및 브롬화 반응을 통해 합성할 수 있다[참고: Yamada, K. 등,Tetrahedron Lett., 2745 (1973); Vyas, G. N. 등,Org. Syn. Coll. Vol. 4, 836 (1963); 및 Kalir, A.,Org. Syn. Coll. Vol. 5, 825 (1973); 대한민국 공개 제 98-83587 호; 대한민국 공개 제 99-15785 호; 및 국제 공개 WO 99/07665 호].Methyl ( 2E ) -3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate represented by the formula (2a) is a well-known method, as shown in Scheme 2 below. From methylphenylacetic acid via esterification and formylation, methylation, and bromination reactions. Yamada, K. et al . , Tetrahedron Lett. , 2745 (1973); Vyas, GN et al . , Org. Syn. Coll. Vol. 4 , 836 (1963); And Kalir, A., Org. Syn. Coll. Vol. 5 , 825 (1973); Republic of Korea Publication No. 98-83587; Republic of Korea Publication No. 99-15785; And International Publication WO 99/07665.
화학식 2b로 표시되는 메틸 (2E)-2-메톡시이미노-2-(2'-브로모메틸)페닐아세테이트는 잘 알려진 공지된 방법에 의해 하기 반응식 3에 도시한 바와 같이 2-브로모톨루엔으로부터 옥살산화 및 축합, 알킬화 및 브롬화 반응을 통해 합성할 수 있다[참고: Rambaud, M.등,Synthesis, 564 (1988); 대한민국 공개 제 98-83587 호; 대한민국 공개 제 99-15785 호; 및 국제 공개 WO 99/07665 호].Methyl of the formula 2b (2 E) -2-methoxy toksiyi diamino-2- (2'-bromomethyl) phenyl acetate is well-known to by methods known 2-bromo-toluene as shown in Scheme 3 From oxalation and condensation, alkylation and bromination reactions. Rambaud, M. et al., Synthesis , 564 (1988); Republic of Korea Publication No. 98-83587; Republic of Korea Publication No. 99-15785; And International Publication WO 99/07665.
한편, 본 발명에서 출발 물질로서 사용되는 화학식 3의 옥심계 화합물은 바람직하게는, R1에 따라 하기 화학식 3a(R1=H), 3b(R1=CH3) 및 3c(R1=CF3)의 화합물을 포함한다.On the other hand, oxime compounds of formula (3) used as a starting material in the present invention, preferably, the following formula according to R 1 3a (R 1 = H ), 3b (R 1 = CH 3) and 3c (R 1 = CF 3 ) compounds of the present invention.
화학식 3의 옥심계 화합물은 잘 알려진 공지된 방법에 의해 하기 반응식 4에 도시한 바와 같이 3-히드록시벤즈알데히드, 3-히드록시아세토페논, 및 3-히드록시-2',2',2'-트리플루오르아세토페논을 각각의 원료로 사용하여 벤질화 및 축합반응을 통해 합성할 수 있다[참고: Kuhn, R. 등,Chem. Ber. 90, 203(1957), Fletcher, H. G. 등,Methods Carbohydr. Chem., II, 166(1963); Freedman, H. H. 등,Tetrahedron Lett., 3251(1975) 및 Lichtenhaler, F. W. 등,Tetrahedron Lett., 1425(1980); Sugg, E. E. 등,J. Org. Chem., 50, 5032(1985)].The oxime compounds of formula 3 are prepared by the well-known methods, as shown in Scheme 4 below, 3-hydroxybenzaldehyde, 3-hydroxyacetophenone, and 3-hydroxy-2 ', 2', 2'- Trifluoroacetophenone can be synthesized through benzylation and condensation using each raw material. See Kuhn, R. et al. , Chem. Ber. 90 , 203 (1957), Fletcher, HG et al . , Methods Carbohydr. Chem. , II, 166 (1963); Freedman, HH et al . , Tetrahedron Lett. , 3251 (1975) and Lichtenhaler, FW et al . , Tetrahedron Lett. , 1425 (1980); Sugg, EE et al . , J. Org. Chem., 50 , 5032 (1985)].
상기 식에서, R1은 상기 정의한 바와 같다.Wherein R 1 is as defined above.
본 발명에서 중간체로 생성되는 화학식 4의 화합물은 바람직하게는, 반응물질로 사용된 화학식 2a 및 2b의 브롬화물과 화학식 3a, 3b 및 3c의 옥심계 화합물에 각각 상응하게, 하기 화학식 4a(X=CH, R1=H), 4b(X=CH, R1=CH3), 4c(X=CH,R1=CF3), 4d(X=N, R1=H), 4e(X=N, R1=CH3) 및 4f(X=N, R1=CF3)의 화합물을 포함할 수 있다.The compound of formula 4 produced as an intermediate in the present invention preferably corresponds to the bromide of formulas 2a and 2b and the oxime compounds of formulas 3a, 3b and 3c used as reactants, respectively. CH, R 1 = H), 4b (X = CH, R 1 = CH 3 ), 4c (X = CH, R 1 = CF 3 ), 4d (X = N, R 1 = H), 4e (X = N, R 1 = CH 3 ) and 4f (X = N, R 1 = CF 3 ).
화학식 4의 화합물은, 하기 반응식 5에 도시한 바와 같이, 화학식 2의 브롬화물과 화학식 3의 옥심계 화합물을 염기 존재하에 반응시킴으로써 고수율로 얻을 수 있다.The compound of Formula 4 can be obtained in high yield by reacting the bromide of Formula 2 with the oxime compound of Formula 3 in the presence of a base, as shown in Scheme 5 below.
상기 반응식에서, X 및 R1은 상기 정의한 바와 같다.In the above scheme, X and R 1 are as defined above.
상기 반응에서 화학식 2의 브롬화물과 화학식 3의 옥심계 화합물의 사용량은등몰량이며, 염기는 이들 화합물에 대하여 1 내지 2 당량을 사용하는 것이 바람직하다. 이때 사용할 수 있는 염기로는 수소화나트륨,t-부톡시화칼륨, 탄산나트륨, 탄산칼륨 등의 무기 염기 및 트리에틸아민, 피리딘 등의 유기 염기가 사용 가능하다. 또한, 용제로서 아세톤, 벤젠, 톨루엔, 테트라히드로푸란, 아세토니트릴, 디클로로메탄 또는 디메틸포름아미드 등을 사용할 수 있으며, 반응 온도는 실온에서부터 100℃ 이내의 온도가 적당하고, 반응의 종료 시점은 반응물이 모두 소비된 때이며 이 시기는 박막 크로마토그래피(TLC)에 의해 쉽게 확인할 수 있다.In the above reaction, the amount of the bromide of Formula 2 and the oxime compound of Formula 3 is equimolar, and it is preferable to use 1 to 2 equivalents of the base with respect to these compounds. In this case, inorganic bases such as sodium hydride, t -butoxylate, sodium carbonate and potassium carbonate, and organic bases such as triethylamine and pyridine can be used. In addition, acetone, benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane, or dimethylformamide may be used as the solvent, and the reaction temperature is appropriate from room temperature to 100 ° C. All are consumed and this time can be easily identified by thin layer chromatography (TLC).
또한, 본 발명에서 중간체인 화학식 5a의 페놀성 에스테르계 화합물은 공지된 방법에 의해 하기 반응식 6에 도시한 바와 같이 화학식 4의 화합물을 원료로 하여 탈벤질화 반응을 통해 합성할 수 있다[참고: Hartung, W. H. 등,Org. React., 7, 263 (1953); Heathcock, C. H. 등,J. Amer. Chem. Soc., 93, 1746 (1971); 및 Bindra, J. S.,J. Org. Chem. Vol. 43, 3240 (1978)].In addition, the phenolic ester compound of Formula 5a, which is an intermediate in the present invention, may be synthesized through a debenzylation reaction using a compound of Formula 4 as a raw material, as shown in Scheme 6, by a known method. Hartung, WH et al . , Org. React., 7 , 263 (1953); Heathcock, CH et al . , J. Amer. Chem. Soc., 93 , 1746 (1971); And Bindra, JS, J. Org. Chem. Vol. 43 , 3240 (1978).
상기 식에서, X 및 R1은 상기 정의한 바와 같다.Wherein X and R 1 are as defined above.
또한, 본 발명에서 중간체로 생성되는 화학식 5a의 페놀성 에스테르계 화합물은 바람직하게는, 반응물질로 사용된 화학식 4a 내지 4f의 화합물에 각각 상응하게, 하기 화학식 5aa(X=CH, R1=H), 5ab(X=CH, R1=CH3), 5ac(X=CH, R1=CF3), 5ad(X=N, R1=H), 5ae(X=N, R1=CH3) 및 5af(X=N, R1=CF3)의 화합물을 포함할 수 있다.In addition, the phenolic ester compound of Formula 5a produced as an intermediate in the present invention preferably corresponds to the compounds of Formulas 4a to 4f used as reactants, respectively, in Formula 5aa (X = CH, R 1 = H). ), 5ab (X = CH, R 1 = CH 3 ), 5ac (X = CH, R 1 = CF 3 ), 5ad (X = N, R 1 = H), 5ae (X = N, R 1 = CH 3 ) and 5af (X = N, R 1 = CF 3 ).
화학식 6의 불소화 프로페닐계 화합물은 하기 반응식 7에 도시한 바와 같이 할로겐화물을 원료로 하여 그리니아 반응, 및 비티히 반응 등 공지된 방법을 경유하여 합성할 수 있다[참고: Herkes, F. E. 등,J. Org. Chem.,32, 1311 (1967); 및 Wheaton, G. A. 등,J. Org. Chem.,48, 917 (1983)].The fluorinated propenyl compound of the formula (6) can be synthesized through a known method such as Greenian reaction, Wittig reaction, etc., using a halide as a raw material as shown in Scheme 7 below [Reference: Herkes, FE, J. Org. Chem. , 32 , 1311 (1967); And Wheaton, GA et al . , J. Org. Chem. , 48 , 917 (1983).
상기 식에서, R2는 상기 정의한 바와 같고, Z는 염소 또는 취소이다.Wherein R 2 is as defined above and Z is chlorine or cancellation.
화학식 5a의 페놀성 에스테르계 화합물과 화학식 6의 불소화 프로페닐계 화합물을 하기 반응식 8에 도시한 바와 같이 염기 존재하에 반응시켜 본 발명의 목적 화합물인 화학식 1a의 화합물을 제조할 수 있다.The phenolic ester compound of Formula 5a and the fluorinated propenyl compound of Formula 6 may be reacted in the presence of a base as shown in Scheme 8 to prepare a compound of Formula 1a, which is the target compound of the present invention.
상기 식에서, X, R1및 R2는 상기 정의한 바와 같다.Wherein X, R 1 and R 2 are as defined above.
상기 반응에서 화학식 5a의 화합물과 화학식 6의 화합물과의 사용량은 등몰량이며, 염기는 이들 화합물에 대하여 1 내지 2 당량 사용하는 것이 바람직하다. 이때 용제로서 벤젠, 톨루엔, 테트라히드로푸란, 아세토니트릴, 디클로로메탄 또는 디메틸포름아미드 등을 사용할 수 있다. 염기로는 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨 등의 수용액을 비롯하여 수소화나트륨,t-부톡시화칼륨 등의 무기 염기 및 트리에틸 아민, 피리딘 등의 유기 염기가 사용가능하다. 반응 온도는 실온에서부터 100℃ 이내의 온도가 적당하며, 반응의 종료 시점은 반응물이 전부 소비된 때이며 이는 박막 크로마토그래피(TLC) 등에 의해 쉽게 확인할 수 있다.In the above reaction, the amount of the compound represented by the formula (5a) and the compound represented by the formula (6) is equimolar, and it is preferable to use 1 to 2 equivalents of the base with respect to these compounds. At this time, benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane or dimethylformamide may be used as the solvent. Examples of the base include aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, inorganic bases such as sodium hydride and t -butoxylate, and organic bases such as triethyl amine and pyridine. The temperature of the reaction is suitably within room temperature to 100 ℃, the end of the reaction is when the reaction is consumed, which can be easily confirmed by thin layer chromatography (TLC).
또한, 본 발명에 따른 화학식 1의 화합물 중 Y가 NH인 하기 화학식 1b의 프로펜아미드 화합물은, 공지된 방법에 의해 하기 반응식 9에 도시한 바와 같이 화학식 5a의 페놀성 에스테르계 화합물을 아민과 통상적인 방법에 의해 반응시켜 화학식 5b의 페놀성 아미드계 화합물을 얻고 이를 반응식 8에 도시한 바와 같이 화학식 6의 불소화 프로페닐계 화합물과 염기 존재하에 반응시킴으로써 얻을 수 있다.In addition, the propeneamide compound of formula (1b) wherein Y is NH in the compound of formula (1) according to the present invention, by using a known method, the phenolic ester compound of formula (5a) It is obtained by reacting by the phosphorus method to obtain a phenolic amide compound represented by the formula (5b) and reacting the fluorinated propenyl compound represented by the formula (6) in the presence of a base as shown in Scheme 8.
상기 식에서, X, R1및 R2는 상기 정의한 바와 같다.Wherein X, R 1 and R 2 are as defined above.
예를 들면, 화학식 5a의 페놀성 에스테르 화합물을 메탄올과 같은 알콜 중에서 메틸 아민과 같은 알킬 아민과 반응시켜 페놀성 아미드 화합물을 합성할 수 있으며, 아민은 상기 에스테르 화합물에 대하여 과량 사용하는 것이 바람직하다. 이때, 사용될 수 있는 용제로는 메탄올을 비롯한 알콜류외에 아세토니트릴, 디클로로메탄 또는 디메틸포름아미드 등이 포함되며, 반응에 사용할 수 있는 아민류로는 메틸아민 및 1급 알킬아민이 포함될 수 있으며, 이로써 다양한 아미드를 제조할 수 있다. 반응 온도는 실온에서부터 용제의 비점 이내의 온도가 적당하다.For example, the phenolic ester compound of formula 5a may be reacted with an alkyl amine such as methyl amine in an alcohol such as methanol to synthesize a phenolic amide compound, and the amine is preferably used in excess of the ester compound. In this case, solvents that may be used include acetonitrile, dichloromethane, or dimethylformamide in addition to alcohols including methanol, and amines that may be used for the reaction may include methylamine and primary alkylamine, and thus various amides. Can be prepared. The reaction temperature is preferably a temperature within room temperature from the boiling point of the solvent.
화학식 5b의 페놀성 아미드계 화합물은 바람직하게는, 반응물질로 사용된 화학식 5aa 내지 5af의 화합물에 각각 상응하게, 하기 화학식 5ba(X=CH, R1=H), 5bb(X=CH, R1=CH3), 5bc(X=CH, R1=CF3), 5bd(X=N, R1=H), 5be(X=N, R1=CH3) 및 5bf(X=N, R1=CF3)의 화합물을 포함할 수 있다.The phenolic amide compound of Formula 5b preferably corresponds to the compounds of Formulas 5aa to 5af used as reactants, respectively, of Formulas 5ba (X = CH, R 1 = H), 5bb (X = CH, R 1 = CH 3 ), 5bc (X = CH, R 1 = CF 3 ), 5bd (X = N, R 1 = H), 5be (X = N, R 1 = CH 3 ) and 5bf (X = N, R 1 = CF 3 ) may be included.
본 발명의 목적 화합물인 화학식 1의 화합물은 분자내의 세곳에 이중 결합을 가지고 있다. 이들 가운데 가교를 구성하는 옥심의 이중결합에 대한 이성질체를 제외하고 나머지 두 개의 이중결합에 대한 이성질체만을 고려할 경우, 치환기 메톡시기가 이중 결합에 대하여 어떠한 입체적 배치를 갖느냐에 따라, 또한 불소와 트리플루오르메틸기가 이중 결합에 대하여 어떠한 입체적 배치를 갖느냐에 따라, 이론적으로 각각 하기 화학식 1c 내지 1f의 트란스, 트란스(E,E) 이성체, 트란스, 시스(E,Z) 이성체, 시스, 트란스(Z,E) 이성체, 및 시스, 시스(Z,Z) 이성체의 네가지 이성질체가 존재할 수 있다.The compound of formula 1, which is the target compound of the present invention, has a double bond in three places in the molecule. Considering only the isomers for the remaining two double bonds except the isomers for the double bond of the oxime constituting the crosslinking, depending on the steric configuration of the substituent methoxy group for the double bond, the fluorine and trifluoromethyl groups Depending on what steric configuration the double bond has, theoretically the trans, trans ( E, E ) isomer, trans, cis ( E, Z ) isomer, cis, trans ( Z, E ) There may be four isomers of isomers and cis, cis ( Z, Z ) isomers.
상기 식에서, X, Y, R1및 R2는 상기 정의한 바와 같다.Wherein X, Y, R 1 and R 2 are as defined above.
본 발명에 따른 화학식 1의 화합물을 제조하는 데 있어서, 화학식 2의 브롬화물의 제조시 생성되는 이성질체를 정제하지 않고 혼합물 상태로 원료로서 사용할 경우 트란스, 트란스(E,E) 이성체(화학식 1c) 와 트란스, 시스(E,Z) 이성체(화학식 1d)를 주 생성물로 하고 부생성물로서 시스, 트란스(Z,E) 이성체(화학식 1e)와 시스, 시스(Z,Z) 이성체(화학식 1f)를 포함하는 혼합생성물을 얻을 수 있다.In preparing the compound of Formula 1 according to the present invention, when the isomers produced in the preparation of the bromide of Formula 2 are used as raw materials in a mixture without purification, the trans, trans ( E, E ) isomers (Formula 1c) and The trans, cis ( E, Z ) isomer (Formula 1d) is the main product and includes the cis, trans ( Z, E ) isomer (Formula 1e) and the cis, cis ( Z, Z ) isomer (Formula 1f) A mixed product can be obtained.
그러나, 본 발명에서는, 화학식 1의 화합물 가운데 X가 CH이고 Y가 O인 화합물은 합성 중간체인 메틸 3-메톡시-2-(2'-메틸)페닐-2-프로페노에이트의 합성시 (반응식 2 참조) 생성되는 이성질체 가운데 트란스 이성질체만을 분리하여 다음 반응에 사용하였으며, 또한 X가 N이고 Y가 O인 화합물은 합성 중간체인 2-메톡시이미노-2-(2'-메틸)페닐아세테이트의 합성시(반응식 3 참조) 액상과 고상의 두가지 이성질체가 1:1로 생성되나 고상의 이성질체를 X-선 결정법으로 구조결정한 결과 트란스 이성질체임이 밝혀져 이들 이성질체만을 분리 정제하여 다음 반응에 사용함으로써, 본 발명의 최종 생성물은, 상기 트란스 이성질체와 화학식 6의 불소화 프로페닐계 화합물과의 반응으로부터 생성되는E,E-이성질체(화학식 1c)와E,Z-이성질체(화학식 1d)의 두가지 이성질체의 혼합물로서 얻어지며, 이들 이성질체는19F-NMR 분석(기준물질: CFCl3) 결과 비닐기에 치환된 불소와 트리플루오르메틸기의 불소의 화학적 이동(chemical shift) 및 이들의 커플링 상수(coupling constant)에 의해 확인되었다. 즉,E,E-체(화학식 1c)의 경우 비닐기에 치환된 불소는 -75.916 ppm 위치에 12.22 Hz 의 커플링 상수를 가지는 사중선으로 나타나며, 트리플루오르메틸기의 불소는 -58.714 ppm 위치에 12.267 Hz 의 커플링 상수를 가지는 이중선으로 나타난다. 그리고,E,Z-체(화학식 1d)의 경우 비닐기에 치환된 불소는 -76.313 ppm 위치에 23.93 Hz 의 커플링 상수를 가지는 사중선으로 나타나며, 트리플루오르메틸기의 불소는 -58.518 ppm 위치에 24.676 Hz 의 커플링 상수를 가지는 이중선으로 나타나는 것을 확인하였다. 한편,E,E-체(화학식 1c)와E,Z-체(화학식 1d)의 비율은 약 1:2로서19F-NMR 상의 F 적분치로 계산되어 진다.However, in the present invention, among the compounds of the formula (1), X is CH and Y is O in the synthesis of methyl 3-methoxy-2- (2'-methyl) phenyl-2-propenoate as a synthetic intermediate. 2) Only the trans isomer was isolated from the resulting isomers and used in the following reaction. In addition, the compound of X is N and Y is O was synthesized from 2-methoxyimino-2- (2'-methyl) phenylacetate as a synthetic intermediate. The two isomers of the liquid phase and the solid phase are produced in a 1: 1 ratio, but when the solid phase isomer was determined by X-ray crystallography, it was found to be a trans isomer, and only these isomers were separated and purified for use in the next reaction. The final product is composed of two isomers of E, E -isomer (Formula 1c) and E, Z -isomer (Formula 1d) generated from the reaction of the trans isomer with the fluorinated propenyl compound of formula (6). Obtained as a mixture, these isomers were subjected to 19 F-NMR analysis (reference material: CFCl 3 ) to chemical shifts of fluorine and trifluoromethyl groups substituted with vinyl groups and their coupling constants. It was confirmed by That is, in the case of the E, E -form (Formula 1c), the fluorine substituted in the vinyl group is represented by a quartet having a coupling constant of 12.22 Hz at the position of -75.916 ppm, and the fluorine of the trifluoromethyl group is 12.267 Hz at the position of -58.714 ppm. It appears as a double line with a coupling constant of. In the case of the E, Z -form (Formula 1d), the fluorine substituted in the vinyl group is represented by a quartet having a coupling constant of 23.93 Hz at the position of -76.313 ppm, and the fluorine of the trifluoromethyl group is 24.676 Hz at the position of -58.518 ppm. It was confirmed that it appeared as a double line having a coupling constant of. On the other hand, the ratio of the E, E -form (Formula 1c) and the E, Z -form (Formula 1d) is about 1: 2, which is calculated as the F integral value on the 19 F-NMR.
결국 본 발명의 방법에 따르면, 화학식 1의 화합물은 실제로E,Z-체(화학식1d)를 주생성물로 하고E,E-체(화학식 1c)가 부생성물인 혼합물로서 얻어진다.Eventually, according to the method of the present invention, the compound of formula 1 is actually obtained as a mixture in which the E, Z -form (Formula 1d) is the main product and the E, E -form (Formula 1c) is a by-product.
한편, 본 발명에 따른 화학식 1의 화합물은 우수한 살균 활성을 가지므로, 본 발명에서는 이를 유효 성분으로 포함하는 살균제 조성물을 제공한다. 본 발명에 따른 조성물은 화학식 1의 화합물 1종 이상을 적당한 담체, 희석제와 혼합하여 적당한 제형, 예를 들면, 유제, 수화제, 분제, 입제 등의 형태로 조제하여 사용할 수 있는데, 이때 유효 성분의 함유 비율은 예를 들어 그 조제가 유제나 수화제인 경우에는 10 내지 90 중량%, 분제일 경우에는 0.1 내지 10 중량%, 그리고 입제인 경우에는 1 내지 30 중량%인 것이 바람직하지만, 그 조제의 사용 목적에 따라 다소의 변화도 가능하다.On the other hand, since the compound of Formula 1 according to the present invention has excellent bactericidal activity, the present invention provides a bactericidal composition comprising it as an active ingredient. The composition according to the present invention may be used by mixing one or more compounds of the formula (1) with a suitable carrier and diluent in the form of a suitable formulation, for example, emulsions, hydrates, powders, granules, etc. The ratio is preferably, for example, 10 to 90% by weight if the preparation is an emulsion or a hydrating agent, 0.1 to 10% by weight if it is a powder, and 1 to 30% by weight if the preparation is used. Some changes are possible.
본 발명에 따른 조성물에 사용하기에 적당한 담체는 액체 담체 및 고체 담체가 사용가능하다. 액체 담체로는 물, 알콜류(메탄올 등 1가 알콜, 에틸렌글리콜 등 2가 알콜, 글리세린 등 3가 알콜), 케톤류(아세톤, 메틸에틸케톤 등), 에테르류(디옥산, 테트라히드로푸란, 셀로솔브 등), 지방족 탄화수소류(가솔린, 케로센 등), 할로겐화 탄화수소류(클로로포름, 사염화탄소 등), 산 아미드 류(디메틸포름아미드 등), 에스테르류(에틸 아세테이트, 부틸 아세테이트, 지방산 글리세린 에스테르 등), 아세토니트릴 등이 있으며 본 발명에서는 이들을 단독으로 또는 2 종 이상 혼합하여 사용할 수 있다. 또한 고체 담체로는 광물성 입자(카올린, 점토, 벤토나이트, 산성백토, 활석, 규석, 실리카, 모래 등), 식물성 분말(목본 등) 등의 기타 광물질 입자를 사용할 수 있다. 또한 본 발명의 조성물에는 유화제, 접착제, 분산제 또는 침윤제 등을 사용할 수 있는데, 예를 들면 지방산 소오다 폴리옥시 알킬에스테르류, 알킬 설포네이트류, 폴리에틸렌글리콜에스테르류 등과 같은 비이온성, 음이온성 또는 양이온성 계면활성제를 사용할 수 있다.Suitable carriers for use in the compositions according to the invention include liquid carriers and solid carriers. Examples of liquid carriers include water, alcohols (monohydric alcohols such as methanol, dihydric alcohols such as ethylene glycol, trihydric alcohols such as glycerin), ketones (acetone, methyl ethyl ketone, etc.), ethers (dioxane, tetrahydrofuran, and cellosolves. Etc.), aliphatic hydrocarbons (gasoline, kerosene, etc.), halogenated hydrocarbons (chloroform, carbon tetrachloride, etc.), acid amides (dimethylformamide, etc.), esters (ethyl acetate, butyl acetate, fatty acid glycerin esters, etc.), aceto Nitrile and the like, and in the present invention, these may be used alone or in combination of two or more thereof. As the solid carrier, other mineral particles such as mineral particles (kaolin, clay, bentonite, acid clay, talc, silica, silica, sand, etc.), vegetable powders (wood, etc.) can be used. In addition, an emulsifier, an adhesive, a dispersant, or a wetting agent may be used in the composition of the present invention. For example, nonionic, anionic or cation such as fatty acid soda polyoxy alkyl esters, alkyl sulfonates, polyethylene glycol esters, and the like. A surfactant can be used.
그 밖에도 본 발명의 조성물에는 다른 종류의 농화학적 활성 성분, 예를 들면 살충제, 제초제, 식물생장조절제, 살균제 등을 혼합하여 사용할 수 있고, 필요에 따라서는 비료 또는 생물농약 등을 함께 혼합하여 사용할 수도 있다.In addition, the composition of the present invention may be used by mixing other types of agrochemically active ingredients, such as insecticides, herbicides, plant growth regulators, fungicides, etc., if necessary, may also be used in combination with fertilizers or biopesticides have.
이하 본 발명을 하기 제조예 및 실시예를 통하여 보다 상세히 설명하나, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following Preparation Examples and Examples, but the present invention is not limited thereto.
본 발명에서 상기 입체이성질체 화합물 중 분리가 가능한 경우에는 분리하여 각각의 화합물에 대한 생리 활성을 평가하였으며, 분리할 수 없는 경우에는 혼합물 형태로 활성을 평가하였다.In the present invention, when the separation is possible among the stereoisomer compounds, the separation was evaluated for physiological activity for each compound, and in the case of separation, the activity was evaluated in the form of a mixture.
제조예 1: 메틸 (2E)-3-메톡시-2-(2'-브로모메틸)페닐-2-프로페노에이트(화학식 2a)의 제조Preparation Example 1 Preparation of Methyl ( 2E ) -3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate (Formula 2a)
단계 1: 메틸 2-메틸페닐아세테이트의 제조Step 1: Preparation of Methyl 2-methylphenylacetate
2-메틸페닐아세트산(30.0g, 0.2mol)을 메탄올(100 ml)에 용해시킨 뒤 산 촉매로서 진한 황산(5ml)을 가하고, 생성 혼합물을 6 내지 12 시간 교반하며 가열하였다. 반응액을 냉각시킨 뒤 용매를 감압하에 제거하고, 물로 2 내지 3회 세척한 후 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤, 용매를 감압 하에 제거하고, 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 액상의 화합물로 메틸 2-메틸페닐아세테이트 32.15g을 얻었다(수율98%).2-methylphenylacetic acid (30.0 g, 0.2 mol) was dissolved in methanol (100 ml), then concentrated sulfuric acid (5 ml) was added as the acid catalyst, and the resulting mixture was heated with stirring for 6-12 hours. After cooling the reaction solution, the solvent was removed under reduced pressure, washed 2-3 times with water and extracted with ethyl acetate. After drying the organic layer, the solvent was removed under reduced pressure, and purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give 32.15 g of methyl 2-methylphenyl acetate as a colorless liquid compound ( Yield 98%).
1H-NMR(CDCl3, TMS)δ(ppm): 7.21-7.01(m, 4H), 3.61(s, 3H), 3.60(s, 2H), 2.35(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.21-7.01 (m, 4H), 3.61 (s, 3H), 3.60 (s, 2H), 2.35 (s, 3H)
MS(m/e): 164 (M+, 42), 133(100), 31(82)MS (m / e): 164 (M + , 42), 133 (100), 31 (82)
단계 2: 메틸 3-히드록시-2-(2'-메틸)페닐-2-프로페노에이트의 제조Step 2: Preparation of Methyl 3-hydroxy-2- (2'-methyl) phenyl-2-propenoate
단계 1에서 얻은 메틸 2-메틸페닐아세테이트(24.6g, 0.15mol)를 메톡시화 나트륨(24.3g, 0.45mol)과 혼합한 뒤, 톨루엔(300ml)을 가하고, 냉각하에 포름산메틸(27.02g, 0.45mol)을 30분 내지 1시간에 걸쳐 적가하며 교반하였다. 반응액을 상온에서 12 시간 교반한 뒤 물로 2 내지 3회 추출하였다. 수층을 진한 염산 용액으로 산성화한 뒤에 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤 용매를 감압 제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=9:1)로 정제하여 무색 액상의 화합물로 메틸 3-히드록시-2-(2'-메틸)페닐-2-프로페노에이트 27.36g을 얻었다(수율 95%).Methyl 2-methylphenylacetate (24.6 g, 0.15 mol) obtained in step 1 was mixed with sodium methoxylated (24.3 g, 0.45 mol), then toluene (300 ml) was added and methyl formate (27.02 g, 0.45 mol) under cooling Was stirred dropwise over 30 minutes to 1 hour. The reaction solution was stirred at room temperature for 12 hours and then extracted with water two to three times. The aqueous layer was acidified with concentrated hydrochloric acid solution and extracted with ethyl acetate. After drying the organic layer, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 9: 1) to give methyl 3-hydroxy-2- (2'-methyl) as a colorless liquid compound. ) 27.36 g of phenyl-2-propenoate was obtained (yield 95%).
1H-NMR(CDCl3, TMS)δ(ppm): 11.92(d, 1H), 7.32-7.01(m, 4H), 3.71(s, 3H), 2.21(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 11.92 (d, 1H), 7.32-7.01 (m, 4H), 3.71 (s, 3H), 2.21 (s, 3H)
MS(m/e): 192 (M+, 26), 160(52), 132(48), 84(100)MS (m / e): 192 (M + , 26), 160 (52), 132 (48), 84 (100)
단계 3: 메틸 3-메톡시-2-(2'-메틸)페닐-2-프로페노에이트의 제조Step 3: Preparation of Methyl 3-methoxy-2- (2'-methyl) phenyl-2-propenoate
단계 2에서 얻은 메틸 3-히드록시-2-(2'-메틸)페닐-2-프로페노에이트(19.2g,0.1mol)를 디메틸설페이트(15.13g, 0.12mol)와 탄산칼륨(13.82g, 0.1mol)을 아세톤(200ml)과 혼합한 뒤 반응액을 12 시간 교반하며 가열하였다. 용매를 제거하고 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤 용매를 감압제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 액상의 화합물로 메틸 3-메톡시-2-(2'-메틸)페닐-2-프로페노에이트 17.1g을 얻었다(수율 83%).Methyl 3-hydroxy-2- (2'-methyl) phenyl-2-propenoate (19.2 g, 0.1 mol) obtained in step 2 was diluted with dimethyl sulfate (15.13 g, 0.12 mol) and potassium carbonate (13.82 g, 0.1 mol) was mixed with acetone (200 ml) and the reaction solution was heated with stirring for 12 hours. Solvent was removed and extracted with ethyl acetate. After drying the organic layer, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1), and methyl 3-methoxy-2- (2'-methyl) was obtained as a colorless liquid compound. ) 17.1 g of phenyl-2-propenoate was obtained (yield 83%).
생성물은 두가지 이성질체의 혼합물로서 이를 분리한 결과 성분비는 각각E(트란스) 이성체(upper spot) 82%,Z(시스) 이성체(down spot) 18%로E체가 주생성물로 얻어졌으며,E체만을 분리하여 다음 단계에 사용하였다.The product is a result of separating them as a mixture of two isomers component ratio has been obtained in each of E (trans) isomer (upper spot) 82%, Z ( cis) isomer (down spot) the major product body E to 18%, and separate only the E-isomer It was used for the next step.
E체(upper spot): 무색 액상의 화합물, 수율 82% E spot (upper spot): colorless liquid compound, yield 82%
1H-NMR(CDCl3, TMS)δ(ppm): 7.51(s, 1H), 7.35-6.98(m, 4H), 3.79(s, 3H), 3.68(s, 3H), 2.21(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.51 (s, 1H), 7.35-6.98 (m, 4H), 3.79 (s, 3H), 3.68 (s, 3H), 2.21 (s, 3H )
MS(m/e): 206 (M+, 10), 176(73), 117(100), 77(57)MS (m / e): 206 (M + , 10), 176 (73), 117 (100), 77 (57)
Z체(down spot): 무색 액상의 화합물, 수율 18% Z spot: colorless liquid compound, yield 18%
1H-NMR(CDCl3, TMS)δ(ppm): 7.34-6.98(m, 4H), 6.50(s, 1H), 3.85(s, 3H), 3.68( s, 3H), 2.21(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.34-6.98 (m, 4H), 6.50 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 2.21 (s, 3H )
MS(m/e): 206 (M+, 8), 176(100), 117(92), 77(30)MS (m / e): 206 (M + , 8), 176 (100), 117 (92), 77 (30)
단계 4: 메틸 (2E)-3-메톡시-2-(2'-브로모메틸)페닐-2-프로페노에이트의 제조Step 4: Preparation of Methyl ( 2E ) -3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate
단계 3에서 분리하여 얻은 메틸 (2E)-3-메톡시-2-(2'-메틸)페닐-2-프로페노에이트(18.54g, 0.09mol)와N-브로모숙신이미드(NBS, 16.0g, 0.09mol)를 사염화탄소(100ml)와 혼합한 뒤 반응액에 라디칼 개시제로 2,2'-아조비스이소부티로니트릴(AIBN, 0.16g, 1mmol)을 가하고 12 시간 교반하면서 가열하였다. 반응액을 냉각시켜 숙신이미드를 여과하여 제거하고, 용매를 감압 하에 제거하여 얻은 유상의 생성물을 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 고상의 화합물로서 (2E)-메틸 3 메톡시-2-(2'-브로모메틸)페닐-2-프로페노에이트 21.73g을 얻었다(수율 85%, 융점: 64-65℃).Methyl (2 E) -3- methoxy-2 obtained by the separation in step 3 (2'-methyl) phenyl-2-propenoate (18.54g, 0.09mol) and N - bromosuccinimide (NBS, 16.0 g, 0.09 mol) was mixed with carbon tetrachloride (100 ml), and 2,2'-azobisisobutyronitrile (AIBN, 0.16 g, 1 mmol) was added to the reaction solution as a radical initiator, followed by heating with stirring for 12 hours. The reaction solution was cooled to remove succinimide, and the solvent was removed under reduced pressure. The oily product was purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give a colorless solid. as the compound (2 E) - methyl 3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate was obtained 21.73g (yield 85%, melting point: 64-65 ℃).
1H-NMR(CDCl3, TMS)δ(ppm): 7.63(s, 1H), 7.51-7.09(m, 4H), 4.40(s, 2H), 3.82(s, 3H), 3.69(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.63 (s, 1H), 7.51-7.09 (m, 4H), 4.40 (s, 2H), 3.82 (s, 3H), 3.69 (s, 3H )
MS(m/e): 284 (M+, 10), 253(12), 205(21), 173(38), 145(100)MS (m / e): 284 (M + , 10), 253 (12), 205 (21), 173 (38), 145 (100)
제조예 2: 메틸 (2E)-2-메톡시이미노-2-(2'-브로모메틸)페닐아세테이트(화학식 2b)의 제조Preparation of methyl (2 E) -2-methoxy toksiyi diamino-2- (2'-bromomethyl) phenyl acetate (Formula 2b): Preparation 2
단계 1: 메틸 2-메틸벤조일포메이트의 제조Step 1: Preparation of Methyl 2-methylbenzoylformate
질소기류하에서 건조시킨 에테르와 마그네슘(5.1g, 0.21mol)을 혼합 교반하면서 2-브로모톨루엔(34.18g, 0.2mol)을 서서히 가하여 그리니아 시약을 제조하였다. 마그네슘과 2-브로모톨루엔이 완전히 반응한 것을 확인한 후에 반응액을 -78℃로 냉각하여 디메틸 옥살레이트(23.6g. 0.2mol)를 서서히 적가하였다. 0.5 시간 교반한 뒤 반응액을 얼음과 혼합하고, 20% 염산 수용액으로 산성화한 후 에테르로 추출하였다. 유기층을 물로 2-3회 세척하여 건조시킨 뒤 용매를 감압 제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=9:1)로 정제하여 무색 액상의 화합물로 메틸 2-메틸벤조일포메이트 24.2g을 얻었다(수율 68%).2-bromotoluene (34.18 g, 0.2 mol) was slowly added while stirring and mixing the ether and magnesium (5.1 g, 0.21 mol) dried under a nitrogen stream to prepare a GREEN reagent. After confirming that magnesium and 2-bromotoluene were completely reacted, the reaction solution was cooled to -78 ° C and dimethyl oxalate (23.6 g. 0.2 mol) was slowly added dropwise. After stirring for 0.5 hour, the reaction mixture was mixed with ice, acidified with 20% aqueous hydrochloric acid solution, and extracted with ether. The organic layer was washed 2-3 times with water, dried, the solvent was removed under reduced pressure, purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 9: 1), and methyl 2-methylbenzoylfo was obtained as a colorless liquid compound. 24.2 g of mate were obtained (yield 68%).
1H-NMR(CDCl3, TMS)δ(ppm): 7.88-7.01(m, 4H), 3.98(s, 3H), 2.65(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.88-7.01 (m, 4H), 3.98 (s, 3H), 2.65 (s, 3H)
MS(m/e): 178 (M+, 21), 119(100), 91(71), 65(37)MS (m / e): 178 (M + , 21), 119 (100), 91 (71), 65 (37)
단계 2: 2-메톡시이미노-2-(2'-메틸)페닐아세테이트의 제조Step 2: Preparation of 2-methoxyimino-2- (2'-methyl) phenylacetate
O-메틸히드록실아민 염산염(8.35g, 0.1mol)과 피리딘(8.1ml 0.1mol)을 메틸알콜(100ml)과 혼합한 뒤 단계 1에서 얻은 메틸 2-메틸벤조일포메이트(17.8g, 0.1mol)를 가하고 12시간 교반하며 가열하였다. 반응액을 감압 하에 건조한 뒤 물과 혼합하고, 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤 용매를 감압 하에 제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 액상의 화합물로서 2-메톡시이미노-2-(2'-메틸)페닐아세테이트 19.04g을 얻었다(수율 92%).Methyl 2-methylbenzoylformate (17.8g, 0.1mol) obtained in step 1 after mixing O -methylhydroxylamine hydrochloride (8.35g, 0.1mol) and pyridine (8.1ml 0.1mol) with methylalcohol (100ml) Was added and heated with stirring for 12 hours. The reaction solution was dried under reduced pressure, mixed with water, and extracted with ethyl acetate. After drying the organic layer, the solvent was removed under reduced pressure and purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give 2-methoxyimino-2- (2'-) as a colorless liquid compound. 19.04 g of methyl) phenyl acetate were obtained (yield 92%).
생성물은 두가지 이성질체의 혼합물로서 이를 분리한 결과 성분비는 각각 액상의 생성물(upper spot) 50%, 고상의 생성물(down spot) 50%로 1:1의 비율로 얻어졌으며, 이를 분리하여 고상의 생성물만을n-헥산으로 재결정하여 융점 63 내지 64℃의 생성물을 X-선 결정법으로 구조결정한 결과E체임을 확인하였다. 이후의 반응단계에서는E체만 사용하였다.The product was a mixture of two isomers, and as a result, the component ratio was obtained in the ratio of 1: 1 in 50% of liquid spot (upper spot) and 50% of solid spot (down spot), respectively. After recrystallization with n -hexane, the product having a melting point of 63 to 64 ° C. was structurally determined by X-ray crystallization, and found to be an E sieve. In the subsequent reaction step, only E was used.
Z체(upper spot): 무색 액상의 화합물 Z spot (upper spot): colorless liquid compound
1H-NMR(CDCl3, TMS)δ(ppm): 7.41-7.15(m, 4H), 4.01(s, 3H), 3.85(s, 3H), 2.45(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.41-7.15 (m, 4H), 4.01 (s, 3H), 3.85 (s, 3H), 2.45 (s, 3H)
MS(m/e): 207 (M+, 8), 176(41), 116(100), 89(62)MS (m / e): 207 (M + , 8), 176 (41), 116 (100), 89 (62)
E체(down spot): 무색 고상의 화합물 E spot (colorless solid)
1H-NMR(CDCl3, TMS)δ(ppm): 7.38-7.05(m, 4H), 4.04(s, 3H), 3.85(s, 3H), 2.19(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.38-7.05 (m, 4H), 4.04 (s, 3H), 3.85 (s, 3H), 2.19 (s, 3H)
MS(m/e): 207 (M+, 11), 176(82), 116(100), 89(70)MS (m / e): 207 (M + , 11), 176 (82), 116 (100), 89 (70)
단계 3: 메틸 (2E)-2-메톡시이미노-2-(2'-브로모메틸)페닐아세테이트의 제조Step 3: Preparation of methyl (2 E) - 2- methoxy Preparation of toksiyi diamino-2- (2'-bromomethyl) phenylacetate
단계 2에서 분리하여 얻은 메틸 (2E)-2-메톡시이미노-2-(2'-메틸)페닐 아세테이트(9.0g, 0.0435mol)와N-브로모숙신이미드(NBS, 7.74g, 0.0435mol)를 사염화탄소(50ml)와 혼합한 뒤 반응액에 라디칼 개시제로 2,2'-아조비스이소부티로니트릴(AIBN, 0.16g, 1mmol)을 가하고 12 시간 교반하며 가열하였다. 반응액을 냉각시키고 숙신이미드를 여과하여 제거하고 용매를 감압 하에 제거하여 얻은 유상의 생성물을 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 액상의 화합물로 메틸 (2E)-2-메톡시이미노-2-(2'-브로모메틸)페닐아세테이트 11.16g을 얻었다(수율 90%)Methyl is obtained by separation in step 2 (2 E) - 2- methoxy toksiyi diamino-2- (2'-methyl) phenylacetate (9.0g, 0.0435mol) and N - bromosuccinimide (NBS, 7.74g, 0.0435 mol) was mixed with carbon tetrachloride (50 ml), and 2,2'-azobisisobutyronitrile (AIBN, 0.16 g, 1 mmol) was added to the reaction solution as a radical initiator, followed by heating with stirring for 12 hours. The reaction mixture was cooled, the succinimide was removed by filtration, and the solvent was removed under reduced pressure. The oily product was purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give a colorless liquid compound. with methyl (2 E) - 2- methoxy toksiyi diamino-2- (2'-bromomethyl) phenylacetate was obtained a 11.16g (90% yield)
1H-NMR(CDCl3, TMS)δ(ppm): 7.62-7.01(m, 4H), 4.39(s, 2H), 4.04(s, 3H), 3.85(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.62-7.01 (m, 4H), 4.39 (s, 2H), 4.04 (s, 3H), 3.85 (s, 3H)
MS(m/e): 285(M+, 46), 252(35), 175(100), 146(94), 116(78)MS (m / e): 285 (M + , 46), 252 (35), 175 (100), 146 (94), 116 (78)
제조예 3: 3-벤질옥시벤즈알독심(화학식 3a)의 제조Preparation Example 3 Preparation of 3-benzyloxybenz aldoxime (Formula 3a)
단계 1: 3-벤질옥시벤즈알데히드의 제조Step 1: Preparation of 3-benzyloxybenzaldehyde
3-히드록시벤즈알데히드(24.4g, 0.2mol)와 벤질클로리드(25.32g, 0.2mol)를 아세톤(500ml)에 혼합한 뒤 탄산나트륨(21.2g, 0.2mol)을 가하고 12 내지 24 시간 교반하며 가열하였다. 반응액을 냉각시킨 뒤 용매를 감압하에 제거하고, 물과 혼합하여 세척한 후 에틸 아세테이트로 2 내지 3회 추출하였다. 유기층을 건조시킨 뒤, 용매를 감압 하에 제거하고, 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=9:1)로 정제하여 무색 액상의 화합물로 3-벤질옥시벤즈알데히드 35.6g을 얻었다(수율 84%).3-hydroxybenzaldehyde (24.4g, 0.2mol) and benzyl chloride (25.32g, 0.2mol) were mixed in acetone (500ml), sodium carbonate (21.2g, 0.2mol) was added and heated with stirring for 12 to 24 hours. . After the reaction solution was cooled, the solvent was removed under reduced pressure, mixed with water, washed, and extracted with ethyl acetate two to three times. After drying the organic layer, the solvent was removed under reduced pressure and purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 9: 1) to give 35.6 g of 3-benzyloxybenzaldehyde as a colorless liquid compound ( Yield 84%).
1H-NMR(CDCl3, TMS)δ(ppm): 10.01(s, 1H), 7.67-7.18(m, 9H), 5.14(s, 2H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 10.01 (s, 1H), 7.67-7.18 (m, 9H), 5.14 (s, 2H)
MS(m/e): 212 (M+, 32), 121(73), 91(100)MS (m / e): 212 (M + , 32), 121 (73), 91 (100)
단계 2: 3-벤질옥시벤즈알독심의 제조Step 2: Preparation of 3-benzyloxybenz aldoxime
단계 1에서 얻은 3-벤질옥시벤즈알데히드(31.8g, 0.15mol)와 히드록실아민염산염(11.47g, 0.165mol)을 메틸알콜(200ml)에 혼합하고 피리딘(13.35ml, 0.165mol)을 가하여, 1시간에 걸쳐 가열 환류시켰다. 반응액을 물과 혼합하여 에틸 아세테이트로 추출하였다. 유기층을 무수 황산마그네슘으로 건조시킨 뒤 용매를 감압 제거하여 얻어지는 백색 고상의 화합물을n-헥산(100ml)으로 세척하여 생성물인 3-벤질옥시벤즈알독심 30.3g을 얻었다(수율 89%, 융점 58-59℃).3-benzyloxybenzaldehyde (31.8g, 0.15mol) and hydroxylamine hydrochloride (11.47g, 0.165mol) obtained in step 1 were mixed with methyl alcohol (200ml) and pyridine (13.35ml, 0.165mol) was added thereto for 1 hour. Heated to reflux over. The reaction solution was mixed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to wash the white solid compound obtained with n -hexane (100 ml) to obtain 30.3 g of 3-benzyloxybenz aldoxime (yield 89%, melting point 58-) 59 ° C.).
1H-NMR(CDCl3, TMS)δ(ppm): 8.62(b, 1H), 8.18(s, 1H), 7.54-7.02(m, 9H), 5.13(s, 2H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 8.62 (b, 1H), 8.18 (s, 1H), 7.54-7.02 (m, 9H), 5.13 (s, 2H)
MS(m/e): 227 (M+, 32), 91(100), 65(45)MS (m / e): 227 (M + , 32), 91 (100), 65 (45)
제조예 4 및 5: 3-벤질옥시페닐메틸옥심(화학식 3b) 및 3-벤질옥시페닐트리플루오르메틸옥심(화학식 3c)의 제조Preparation Examples 4 and 5: Preparation of 3-benzyloxyphenylmethyloxime (Formula 3b) and 3-benzyloxyphenyltrifluoromethyloxime (Formula 3c)
3-히드록시페닐메틸케톤 및 3-히드록시페닐트리플루오르메틸케톤을 각각의 원료로 사용하여 제조예 3에 기재한 바와 유사하게 실시하여 3-벤질옥시페닐메틸옥심 및 3-벤질옥시페닐트리플루오르메틸옥심을 제조하였다.3-benzyloxyphenylmethyloxime and 3-benzyloxyphenyltrifluoro using 3-hydroxyphenylmethylketone and 3-hydroxyphenyltrifluoromethylketone as the starting materials, similar to those described in Preparation Example 3. Methyl oxime was prepared.
화학식 3의 옥심계 화합물의 제조에 있어서 각각의 단계별 중간체 및 최종 생성물의 분석 결과, 융점 및 수율을 하기 표 1에 나타내었다.Analysis of each step intermediate and final product in the preparation of the oxime compound of formula 3, the melting point and the yield are shown in Table 1 below.
제조예 6: 메틸 (2E)-3-메톡시-2-[2-[[(3-벤질옥시페닐)이미노]옥시]메틸페닐]프로페노에이트(화학식 4a)의 제조Preparation Example 6 Preparation of Methyl ( 2E ) -3-methoxy-2- [2-[[(3-benzyloxyphenyl) imino] oxy] methylphenyl] propenoate (Formula 4a)
제조예 1에서 얻은 (2E)-메틸 3-메톡시-2-(2'-브로모메틸)페닐-2-프로페노에이트(5.7g, 0.02mol)와 제조예 3에서 얻은 3-벤질옥시벤즈알독심(4.54g, 0.02mol)을 아세톤(50ml)과 혼합하여 탄산칼륨(2.76g, 0.02mol)을 가하고 24시간 동안 가열 환류하였다. 반응액을 실온으로 냉각시켜 용매를 감압 제거한 다음 물과 혼합하여 에틸 아세테이트(50ml씩)으로 3회에 걸쳐 추출하였다. 유기층을 무수 황산마그네슘으로 건조시킨 후 여과하였다. 여액을 농축하여 실리카겔 칼럼 크로마토그라피(용리제:n-헥산:에틸 아세테이트=4:1)로 분리하여 갈색액상의 생성물 5.86g을 얻었다(수율 68%).(2 E) obtained in Preparation Example 1, methyl 3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate (5.7g, 0.02mol) and 3-benzyloxy obtained in Preparation Example 3 Benz aldoxime (4.54 g, 0.02 mol) was mixed with acetone (50 ml), potassium carbonate (2.76 g, 0.02 mol) was added and heated to reflux for 24 hours. The reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, mixed with water, and extracted three times with ethyl acetate (50 ml each). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give 5.86 g of a brown liquid product (yield 68%).
1H-NMR(CDCl3, TMS)δ(ppm): 8.01(s, 1H), 7.52(s, 1H), 7.51-6.82(m, 13H), 5.18(s, 2H), 5.04(s, 2H), 3.73(s, 3H), 3.61(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 8.01 (s, 1H), 7.52 (s, 1H), 7.51-6.82 (m, 13H), 5.18 (s, 2H), 5.04 (s, 2H ), 3.73 (s, 3H), 3.61 (s, 3H)
MS(m/e): 431(21), 205(39), 189(50), 145(100), 91(67)MS (m / e): 431 (21), 205 (39), 189 (50), 145 (100), 91 (67)
제조예 7 내지 11: 중간체(화학식 4b 내지 4f)의 제조Preparation Examples 7 to 11: Preparation of Intermediate (Formulas 4b to 4f)
제조예 1 및 2에서 얻은 메틸 (2E)-3-메톡시-2-(2'-브로모메틸)페닐-2-프로페노에이트 및 메틸 (2E)-2-메톡시이미노-2-(2'-브로모메틸)페닐아세테이트와 제조 실시예 3 내지 5에서 얻은 옥심계 화합물을 사용하여 상기 제조예 6에 기재한 바와 유사하게 실시하여 본 발명에 사용된 화학식 4b 내지 4f의 중간체를 제조하였다.Methyl (2 E) obtained in Preparation Example 1 and 2-3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate and methyl (2 E) -2-methoxy-2-mino toksiyi Preparation of the intermediates of the formulas 4b to 4f used in the present invention was carried out in the same manner as described in Preparation Example 6 using (2′-bromomethyl) phenylacetate and the oxime compounds obtained in Preparation Examples 3 to 5. It was.
화학식 4의 중간체의 분석 결과 및 수율을 하기 표 2에 나타내었다.Analysis results and yields of the intermediate of formula 4 are shown in Table 2 below.
제조예 12: 메틸 (2E)-3-메톡시-2-[2-[[(3-히드록시벤질)이미노]옥시]메틸페닐]프로페노에이트(화학식 5aa)의 제조Preparation Example 12 Preparation of Methyl ( 2E ) -3-methoxy-2- [2-[[(3-hydroxybenzyl) imino] oxy] methylphenyl] propenoate (Formula 5aa)
제조예 6에서 얻은 메틸 (2E)-3-메톡시-2-[2-[[(3-벤질옥시벤질)이미노]옥시]메틸페닐]프로페노에이트(5.17g, 0.012mol)를 메틸알콜(50ml)에 용해시킨 후 촉매량의 5% 팔라듐카본[Pd(C), Palladium on activated carbon 5%](25mg, 0.1mmol)을 가하고 수소화 반응기를 사용하여 수소를 첨가하면서 6시간 교반 반응시켰다. 반응액을 여과하여 탄소를 제거한 다음 용매인 메틸알콜을 감압 제거한 후 실리카겔 칼럼 크로마토그라피(용리제:n-헥산:에틸 아세테이트=2:1)로 분리하여 갈색 액상의 생성물 3.64g을 얻었다(수율 89%).Methyl obtained in Preparation Example 6 (2 E) -3- methoxy-2- [2 - [[(3-benzyloxy-benzyl) imino] oxy] phenyl] propenoate (5.17g, 0.012mol), methyl alcohol After dissolving in (50ml), 5% palladium carbon [Pd (C), Palladium on activated carbon 5%] (25mg, 0.1mmol) was added and stirred for 6 hours while adding hydrogen using a hydrogenation reactor. The reaction solution was filtered to remove carbon, and then the solvent was removed under reduced pressure, and the solvent was removed under reduced pressure. Then, silica gel column chromatography (eluent: n -hexane: ethyl acetate = 2: 1) was used to obtain 3.64 g of a brown liquid product (yield 89 %).
1H-NMR(CDCl3, TMS)δ(ppm): 8.02(s, 1H), 7.54(s, 1H), 7.53-6.84(m, 8H), 6.48(b, 1H), 5.14(s, 2H),3.78(s, 3H), 3.67(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 8.02 (s, 1H), 7.54 (s, 1H), 7.53-6.84 (m, 8H), 6.48 (b, 1H), 5.14 (s, 2H ), 3.78 (s, 3H), 3.67 (s, 3H)
MS(m/e): 341(41), 250(37), 189(57), 145(100), 103(20)MS (m / e): 341 (41), 250 (37), 189 (57), 145 (100), 103 (20)
제조예 13 내지 17: 페놀성 에스테르계 중간체(화학식 5ab 내지 5af)의 제조Preparation Examples 13 to 17 Preparation of Phenolic Ester Intermediates (Formulas 5ab to 5af)
제조예 7 내지 11에서 얻은 화학식 4의 중간체를 사용하여 제조예 12에 기재한 바와 유사하게 실시하여 본 발명에 사용된 화학식 5ab 내지 5af의 페놀성 에스테르계 중간체를 제조하였다.A phenolic ester intermediate of Formulas 5ab to 5af used in the present invention was prepared in a similar manner as described in Preparation Example 12 using the intermediate of Formula 4 obtained in Preparation Examples 7-11.
화학식 5a의 페놀성 에스테르 중간체의 분석 결과 및 수율을 하기 표 3에 나타내었다.The analytical results and yields of the phenolic ester intermediates of formula 5a are shown in Table 3 below.
제조예 18:N-메틸 (2E)-3-메톡시-2-[2-[[(3-히드록시페닐)이미노]옥시]메틸페닐]프로펜아미드(화학식 5ba)의 제조Preparation of propenamide (Formula 5ba) N - - methyl (2 E) -3- methoxy-2 - [[(3-hydroxyphenyl) imino] oxy] phenyl 2]: Example 18
제조예 12에서 얻은 메틸 (2E)-3-메톡시-2-[2-[[(3-히드록시페닐)이미노]옥시]메틸페닐]프로페노에이트(3.41g, 0.01mol)를 메틸알콜(50ml)에 용해시킨 후 메틸 아민(40ml, 40% 수용액)을 가하였다. 반응액을 12 시간 교반한 다음에 용매를 감압 제거하고 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤 용매를 감압 제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=2:1)로 정제하여 갈색 액상의 생성물 2.90g을 얻었다(수율 85%).Methyl ( 2E ) -3-methoxy-2- [2-[[(3-hydroxyphenyl) imino] oxy] methylphenyl] propenoate (3.41 g, 0.01 mol) obtained in Preparation Example 12 was prepared using methyl alcohol. After dissolving in (50 ml), methyl amine (40 ml, 40% aqueous solution) was added. After stirring the reaction solution for 12 hours, the solvent was removed under reduced pressure and extracted with ethyl acetate. After drying the organic layer, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 2: 1) to obtain 2.90 g of a brown liquid product (yield 85%).
1H-NMR(CDCl3, TMS)δ(ppm): 8.01(s, 1H), 7.55(s, 1H), 7.54-6.88(m, 8H), 6.53(b, 1H), 6.34(b, 1H), 5.12(s, 2H), 3.81(s, 3H), 2.79(d, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 8.01 (s, 1H), 7.55 (s, 1H), 7.54-6.88 (m, 8H), 6.53 (b, 1H), 6.34 (b, 1H ), 5.12 (s, 2H), 3.81 (s, 3H), 2.79 (d, 3H)
MS(m/e): 340(38), 188(100), 144(72)MS (m / e): 340 (38), 188 (100), 144 (72)
제조예 19 내지 22: 페놀성 아미드계 중간체(화학식 5bb 내지 bf)의 제조Preparation Examples 19 to 22: Preparation of Phenolic Amide Intermediates (Formulas 5bb to bf)
제조예 13 내지 17에서 얻은 페놀성 에스테르계 중간체를 사용하여 상기 제조예 18에 기재한 바와 유사하게 실시하여 본 발명에 사용된 화학식 5bb 내지 5bf의 페놀성 아미드계 중간체를 제조하였다.The phenolic amide intermediates of formulas 5bb to 5bf used in the present invention were prepared in a similar manner as described in Preparation Example 18 using the phenolic ester intermediates obtained in Preparation Examples 13 to 17.
화학식 5b의 페놀성 아미드계 중간체의 분석 결과 및 수율을 하기 표 4에 나타내었다.The analytical results and yields of the phenolic amide intermediates of Formula 5b are shown in Table 4 below.
제조예 24: 2,2-디플루오르-1-트리플루오르메틸스티렌(화학식 6)의 제조Preparation Example 24 Preparation of 2,2-difluoro-1-trifluoromethylstyrene (Formula 6)
단계 1: 2,2,2-트리플루오르메틸페닐케톤의 제조Step 1: Preparation of 2,2,2-trifluoromethylphenylketone
건조된 용기에 질소기류를 통과시키며 마그네슘(5.1g, 0.21mol)과 건조시킨 에테르(300ml)를 가하고 브로모벤젠(31.4g, 0.2mol)을 서서히 적가하여 그리니아시약을 제조하였다. -78℃로 냉각 하에 반응액에 에틸트리플루오르아세테이트 28.4g, 0.2mol)를 적가하고 0.5 내지 1 시간 교반하였다. 반응액을 얼음과 혼합하고 진한 염산으로 산성화하여 에테르로 2 내지 3회 추출하였다. 유기층을 건조시킨 뒤 용매를 감압 하에 제거하고 감압 증류하여 33 mmHg에서 64 내지 65℃의 무색 유상의 생성물인 2,2,2-트리플루오르메틸페닐케톤 24.74g을 얻었다(수율 71%).Nitrogen gas was passed through a dried container, and magnesium (5.1 g, 0.21 mol) and dried ether (300 ml) were added, and bromobenzene (31.4 g, 0.2 mol) was slowly added dropwise to prepare a GREEN reagent. Ethyltrifluoroacetate (28.4 g, 0.2 mol) was added dropwise to the reaction solution while cooling to -78 ° C, and stirred for 0.5 to 1 hour. The reaction solution was mixed with ice, acidified with concentrated hydrochloric acid and extracted 2-3 times with ether. After drying the organic layer, the solvent was removed under reduced pressure and distilled under reduced pressure to obtain 24.74 g of a 2,2,2-trifluoromethylphenyl ketone as a colorless oily product at 33 to 64 DEG C at 33 mmHg (yield 71%).
1H-NMR(CDCl3, TMS)δ(ppm): 7.52-7.12(m, 5H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.52-7.12 (m, 5H)
MS(m/e): 174(M+, 21), 105(100), 77(82), 69(54)MS (m / e): 174 (M + , 21), 105 (100), 77 (82), 69 (54)
단계 2: 2,2-디플루오르-1-트리플루오르메틸스티렌의 제조Step 2: Preparation of 2,2-difluoro-1-trifluoromethylstyrene
질소기류하에서 건조된 테트라히드로푸란(THF, 100ml)과 트리페닐포스핀 C6H5)3P, 26.2g, 0.1mol)을 플라스크에 가하고 반응온도를 10oC 이하로 유지시키며 디브로모디플루오르메탄(CF2Br2, 25.2g, 0.12mol)을 적가하였다. 30분간 교반한 후 단계 1에서 합성한 2,2,2-트리플루오르메틸페닐케톤(8.71g, 0.05mol)을 가하고 48시간 가열 환류하였다. 반응액을 냉각하여 감압증류하여 얻은 유상의 생성물을 재증류하여 44mmHg에서 51 내지 52oC 의 유분인 2,2-디플루오르-1-트리플루오르메틸스티렌 7.07g을 얻었다(무색 액상의 화합물, 수율 68%).Tetrahydrofuran (THF, 100 ml) and triphenylphosphine C 6 H 5 ) 3 P, 26.2 g, 0.1 mol) dried under nitrogen stream were added to the flask, and the reaction temperature was maintained at 10 ° C. or lower. Methane (CF 2 Br 2 , 25.2 g, 0.12 mol) was added dropwise. After stirring for 30 minutes, 2,2,2-trifluoromethylphenylketone (8.71 g, 0.05 mol) synthesized in Step 1 was added and heated to reflux for 48 hours. The reaction mixture was cooled and distilled under reduced pressure to distill the oily product to obtain 7.07 g of 2,2-difluoro-1-trifluoromethylstyrene as an oil of 51 to 52 ° C. at 44 mmHg (colorless liquid compound, yield). 68%).
1H-NMR(CDCl3, TMS)δ(ppm): 7.59-7.31(m, 5H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 7.59-7.31 (m, 5H)
MS(m/e): 208(M+, 48), 84(83), 43(100)MS (m / e): 208 (M + , 48), 84 (83), 43 (100)
제조예 25 내지 42: 불소화 프로페닐계 화합물(화학식 6)의 제조Preparation Examples 25 to 42: Preparation of Fluorinated Propenyl Compound (Formula 6)
제조예 24에서 사용된 4-브로모벤젠 대신에 상응하는 할로겐화물을 사용하여 다양한 치환된 2,2,2-트리플루오르메틸페닐케톤을 제조하였으며, 이를 하기 표 5a에 나타내었다.Various substituted 2,2,2-trifluoromethylphenylketones were prepared using the corresponding halides instead of 4-bromobenzene used in Preparation Example 24, which are shown in Table 5a below.
이어서, 치환된 2,2,2-트리플루오르메틸페닐케톤을 원료로 사용하여 제조예 24의 단계 2에 기재된 바와 유사하게 실시하여, 화학식 6의 불소화 프로페닐계 화합물을 제조하였으며, 이들의 분석 결과를 하기 표 5b에 나타내었다.Subsequently, using a substituted 2,2,2-trifluoromethylphenyl ketone as a raw material, it was carried out in the same manner as described in step 2 of Preparation Example 24 to prepare a fluorinated propenyl compound of the formula (6), the results of their analysis It is shown in Table 5b.
실시예 1: 메틸 (2E)-3-메톡시-2-[2-[[[3-(1-플루오르-3,3,3-트리플루오르-2-페닐-1-프로페닐옥시)페닐]이미노]옥시]메틸페닐]프로페노에이트의 제조Example 1: Methyl ( 2E ) -3-methoxy-2- [2-[[[3- (1-fluoro-3,3,3-trifluoro-2-phenyl-1-propenyloxy) phenyl ] Imino] oxy] methylphenyl] propenoate preparation
건조시킨 용기중에 질소 가스를 통과시키며 제조예 12에서 얻은 메틸 (2E)-3-메톡시-2-[2-[[(3-히드록시페닐)이미노]옥시]메틸페닐]프로페노에이트 (341mg, 1mmol)를 아세토니트릴(10ml)과 혼합한 뒤 수소화나트륨(40mg, 1mmol, 60% 광유 분산액)을 가하였다. 반응액을 30분간 교반한 후에 제조예 24에서 얻은 2,2-디플루오르-1-트리플루오르메틸스티렌(208mg, 1mmol)을 서서히 가하고 상온에서 2 내지 4 시간 교반하였다. 반응액을 물과 혼합하여 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤 용매를 감압 하에 제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 액상의 표제 화합물(화합물 1) 470mg을 얻었다(수율 89%).Methyl ( 2E ) -3-methoxy-2- [2-[[(3-hydroxyphenyl) imino] oxy] methylphenyl] propenoate obtained in Preparation Example 12 by passing nitrogen gas through a dried vessel ( 341 mg, 1 mmol) was mixed with acetonitrile (10 ml) and sodium hydride (40 mg, 1 mmol, 60% mineral oil dispersion) was added. After the reaction solution was stirred for 30 minutes, 2,2-difluoro-1-trifluoromethylstyrene (208 mg, 1 mmol) obtained in Preparation Example 24 was slowly added thereto, followed by stirring at room temperature for 2 to 4 hours. The reaction solution was mixed with water and extracted with ethyl acetate. After drying the organic layer, the solvent was removed under reduced pressure and purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give 470 mg of the title compound (compound 1) as a colorless liquid (yield 89%). .
1H-NMR(CDCl3, TMS)δ(ppm): 8.01(s, 1H), 7.59(s, 1H), 7.58-6.92(m, 13H), 5.18(s, 2H), 3.78(s, 3H), 3.61(s, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 8.01 (s, 1H), 7.59 (s, 1H), 7.58-6.92 (m, 13H), 5.18 (s, 2H), 3.78 (s, 3H ), 3.61 (s, 3 H)
19F-NMR(CDCl3, CFCl3)δ(ppm): -75.916(q, 3F,J=12.22Hz), -58.714(d, 1F, J=12.267Hz)E,E-체, -76.313(q, 3F,J=23.93Hz), -58.518(d, 1F, J=24.676Hz)E,Z-체 19 F-NMR (CDCl 3 , CFCl 3 ) δ (ppm): -75.916 (q, 3F, J = 12.22 Hz), -58.714 (d, 1F, J = 12.267 Hz) E, E -body, -76.313 ( q, 3F, J = 23.93 Hz), -58.518 (d, 1F, J = 24.676 Hz) E, Z -sieve
MS(m/e): 529(M+, 18), 205(59), 189(75), 145(100), 131(25)MS (m / e): 529 (M + , 18), 205 (59), 189 (75), 145 (100), 131 (25)
실시예 18:N-메틸 (2E)-3-메톡시-2-[2-[[[3-(1-플루오르-3,3,3-트리플루오르-2-페닐-1-프로페닐옥시)페닐]이미노]옥시]메틸페닐]프로펜아미드의 제조Example 18 N -methyl ( 2E ) -3-methoxy-2- [2-[[[3- (1-fluor-3,3,3-trifluoro-2-phenyl-1-propenyloxy ) Phenyl] imino] oxy] methylphenyl] propenamide
건조시킨 용기중에 질소 가스를 통과시키며 제조예 18에서 얻은N-메틸 (2E)-3-메톡시-2-[2-[[(3-히드록시페닐)이미노]옥시]메틸페닐]프로펜아미드(170mg, 0.5mmol)를 아세토니트릴(10ml)과 혼합한 뒤 수소화나트륨(20mg, 0.5mmol, 60% 광유 분산액)을 가하였다. 반응액을 30분간 교반한 후에 제조예 24에서 얻은 2,2-디플루오르-1-트리플루오르메틸스티렌(104mg, 0.5mmol)을 서서히 가하고 상온에서 2 내지 4 시간 교반하였다. 반응액을 물과 혼합하여 에틸 아세테이트로 추출하였다. 유기층을 건조시킨 뒤 용매를 감압 제거하고 실리카겔 칼럼크로마토그래피(용리제:n-헥산:에틸 아세테이트=4:1)로 정제하여 무색 액상의 표제 화합물(화합물 18) 243mg을 얻었다(수율 92%). N -methyl ( 2E ) -3-methoxy-2- [2-[[(3-hydroxyphenyl) imino] oxy] methylphenyl] propene obtained in Preparation Example 18 by passing nitrogen gas through a dried vessel. Amide (170 mg, 0.5 mmol) was mixed with acetonitrile (10 ml) and sodium hydride (20 mg, 0.5 mmol, 60% mineral oil dispersion) was added. After the reaction solution was stirred for 30 minutes, 2,2-difluoro-1-trifluoromethylstyrene (104 mg, 0.5 mmol) obtained in Preparation Example 24 was slowly added thereto, followed by stirring at room temperature for 2 to 4 hours. The reaction solution was mixed with water and extracted with ethyl acetate. After drying the organic layer, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n -hexane: ethyl acetate = 4: 1) to give 243 mg of the title compound (compound 18) as a colorless liquid (yield 92%).
1H-NMR(CDCl3, TMS)δ(ppm): 8.01(s, 1H), 7.62(s, 1H), 7.61-7.00(m, 13H), 5.18(s, 2H), 4.17(b, 1H), 3.63(s, 3H), 2.98(d, 3H) 1 H-NMR (CDCl 3 , TMS) δ (ppm): 8.01 (s, 1H), 7.62 (s, 1H), 7.61-7.00 (m, 13H), 5.18 (s, 2H), 4.17 (b, 1H ), 3.63 (s, 3H), 2.98 (d, 3H)
MS(m/e): 528(M+, 54), 188(53), 144(100), 103(36), 76(46)MS (m / e): 528 (M + , 54), 188 (53), 144 (100), 103 (36), 76 (46)
실시예 2 내지 17 및 19 내지 122Examples 2 to 17 and 19 to 122
제조예 12 내지 23에서 얻은 페놀성 에스테르계 및 페놀성 아미드계 화합물과 제조예 24 내지 42에서 얻은 불소화 프로페닐계 화합물을 사용하여 실시예 1 및 18에 기재한 바와 유사하게 실시하여 하기 표 6a 내지 6m에 나타낸 바와 같은 화합물(화합물 2 내지 17 및 19 내지 122)을 수득하였다.Using the phenolic ester compound and phenolic amide compound obtained in Preparation Examples 12 to 23 and the fluorinated propenyl compound obtained in Preparation Examples 24 to 42, the procedure was similar to those described in Examples 1 and 18, and the following Tables 6A to Compounds as obtained in 6 m (compounds 2 to 17 and 19 to 122) were obtained.
약효 시험Drug test
본 발명의 화합물의 식물 병원균에 대한 예방 효과 조사를 위하여, 10% 아세톤 용액에 본 발명 화합물을 녹인 후, 일정 크기의 여러가지 기주 식물에 50ml씩 엽면 살포하였다. 이때 용액에는 전착제(Tween-20) 성분이 2250 ppm 농도(벼의 경우 500ppm)가 되도록 첨가하였다. 약제가 살포된 식물을 실내 온도에서 24 시간 동안 방치하여 용매 및 물을 휘산시킨 뒤, 각기 하기 시험예에서 언급한 병원균을 접종하였다. 모든 실험은 2회 반복으로 실시하였다. 이때 약액의 1차 시험 농도(250ppm)에서 방제가가 90% 이상인 경우에는 그 농도를 낮추어 실험하여 2차 시험 농도(50ppm)에서 각각의 균류에 대한 방제효과를 측정하였다.In order to investigate the preventive effect of the compounds of the present invention on plant pathogens, the compound of the present invention was dissolved in a 10% acetone solution, and then 50 ml of foliar spray was applied to various host plants having a predetermined size. At this time, the electrodeposition agent (Tween-20) component was added so as to have a concentration of 2250 ppm (500 ppm in the case of rice). The plants sprayed with the medicament were left at room temperature for 24 hours to volatilize the solvent and water, and then inoculated with the pathogens mentioned in the following test examples, respectively. All experiments were conducted in two replicates. At this time, when the control value was more than 90% at the first test concentration (250ppm) of the chemical solution was tested by lowering the concentration to measure the control effect for each fungus at the second test concentration (50ppm).
실시예 1 내지 122에서 수득한 화합물 모두에 대해 상기 방제 효과를 시험하였으며, 비교를 위해 시노기(Shinogi)사에 의해 제조되어 시판되는 오리브라이트(ORIBRIGHT)와 다우엘란코(DowElanco)사에 의해 제조되어 시판되는 페나리몰(Fenarimol)에 대하여도 동일하게 시험하였다.The control effect was tested on all of the compounds obtained in Examples 1 to 122, and for comparison, manufactured by ORIBRIGHT and DowElanco, manufactured by Shinogi Co., Ltd. for comparison. The same test was conducted for the commercially available Fenarimol.
방제 효과는 사용한 화합물 각각의 식물 병원균에 대한 방제가(Control Value; C.V.) 로서 나타내었고, 방제가는 하기 수학식에 따라 구하였다.The control effect was expressed as Control Value (C.V.) for each plant pathogen of each compound used, and the control value was calculated according to the following equation.
대조구의 이병면적률과 처리구의 이병면적률은 한국 화학연구소의 '식물병병반 면적률 조사기준표(조광연, 1989, 신규 농약 개발을 위한 스크리닝체제 확립, 한국화학 연구소 연구보고서)'에 의해서 산출하였다.The disease area ratio of the control area and that of the treatment area were calculated by the Korea Research Institute of Chemical Research's Criteria for Plant Disease Pathology (CHO Kwang-yeon, 1989, Establishment of Screening System for New Pesticide Development, Korea Research Institute of Chemical Research).
시험예 1: 벼도열병(Rice Blast, RCB)에 대한 시험Test Example 1 Test for Rice Blast (RCB)
병원균인 피리쿨라리아 오라이제 카바라(Pyricularia oryzae Cavara) KA301 균주를 쌀겨 한천배지(쌀겨 20g, 덱스트로스 10g, 아가 15g, 증류수 1ℓ)에 접종하여 26℃ 배양기에서 1 주간 배양하였다. 병원균이 자란 배지를 고무 쓸개로 배지 표면을 긁어 기중 균자를 제거하고, 형광등이 켜진 선반(25℃-28℃)에서 48 시간 동안 배양하여 포자를 형성시켰다. 병균접종을 형성시킨 분생포자를 살균 증류수를 이용하여 일정 농도의 포자 현탁액(포자 농도 1×106개 포자/ml)을 제조한 뒤 벼 도열병에 감수성인 낙동벼(3-4엽기)에 흘러내릴 정도로 충분히 분무 접종하였다. 접종된 벼는 습실상에서 암상태로 24 시간 놓아둔 뒤에 상대 습도 80% 이상이며 온도가 26±2℃인 항온 항습실로 옮겨 5일간 발병을 유도한 후 발병 면적률의 조사를 실시하였다. 병조사는 3-4엽기의 벼유묘에서 최상엽 바로 밑의 완전 전개된 잎에 형성된 병반 면적율을 조사하여 약제 처리하지 않은 표준 이병면적률 대비표에 준하여 조사하였다. Pyricularia oryzae Cavara , a pathogen, was inoculated in rice bran agar medium (rice bran 20g, dextrose 10g, agar 15g, distilled water 1L) and cultured in a 26 ° C. incubator for 1 week. Pathogen-grown medium was scraped off the surface of the medium with a rubber gallbladder to remove airborne bacteria, and cultured for 48 hours on a fluorescent lamp-turned shelf (25 ° C.-28 ° C.) to form spores. The conidia formed with germ inoculation were prepared using a sterile distilled water to produce a certain concentration of spore suspension (spore concentration of 1 × 10 6 spores / ml), and then flowed down to Nakdong rice (3-4 leaf stage) susceptible to rice blasting. Full spray inoculation. The inoculated rice was left in the dark for 24 hours, and then moved to a constant temperature and humidity chamber with a relative humidity of 80% or higher and a temperature of 26 ± 2 ° C, inducing the onset for 5 days, and then examining the area of incidence. The pathology was investigated by comparing the area ratio of lesions formed on the fully developed leaf just below the top lobe in 3-4 leafy rice seedlings according to the standard non-medical treatment.
시험예 2: 벼잎집얼룩병(Rice Sheath Blight, RSB)에 대한 시험Test Example 2: Test for Rice Sheath Blight (RSB)
적당한 양의 밀기울을 1 ℓ배양병에 넣고 멸균한 후 PDA 평판에서 3 일간 자란 병원균인 라이족토니아 솔라니(Rhizoctonia solani)AG-1의 아가 디스크(Agar Disc)를 접종한 후 27±1℃ 항온기에서 7일간 배양하였다. 병접종은 배양된 균사 덩어리를 적당하게 잘게 마쇄하여 2-3엽기의 낙동벼(5cm)가 자란 폿트에 고르게 접종하여 습실상(28±1℃)에서 5 일간 발병을 유도한 후 발병면적률 조사를 실시하였다. 병조사는 2-3엽기의 벼유묘의 잎집에 발명된 병반 면적율을 잎집면적에 대한 병반 면적이 차지하는 비율을 기준으로하여 작성한 표준이병면적률 대비표에 준하여 조사하였다.After sterilizing the appropriate amount of wheat bran in a 1 ℓ bottle and sterilizing, it was inoculated with Agar Disc of Rhizoctonia solani AG-1, which was grown on PDA plates for 3 days, and then incubated at 27 ± 1 ° C. Incubated for 7 days. For vaccination, the cultured mycelium mass was finely ground and inoculated evenly in the pot grown with 2-3 leaves of Nakdong rice (5cm) to induce the onset for 5 days in the wet phase (28 ± 1 ℃). Was carried out. The pathology was based on the ratio of lesion area invented in the foliar of rice seedlings in the 2-3 leaf period based on the ratio of lesion area to leaf area.
시험예 3: 오이 잿빛 곰팡이병(Cucumber Gray Mold Rot, CGM)에 대한 시험Test Example 3: Test for Cucumber Gray Mold Rot (CGM)
오이 잿빛 곰팡이 병으로부터 분리한 보트라이티스 시너레아(Botrytis cinerea)를 감자 한천 배지(PEC)에 접종하고 25℃의 광암상태하에서 15 일간 배양하여 포자를 형성시켰다. 배지에 형성된 포자를 긁어 이를 가제로 걸러서 포자를 수확한 후 포자 농도가 1×106개/ml가 되게 한 뒤 1 엽기 오이에 분무 접종하였다. 이를 20℃ 습실상에서 3일간 습실 처리한 후 본엽 1 엽의 병반 면적율을 조사하였다. 발병 조사는 오이의 잎에 형성된 병반면적율을 조사하여 약제 처리하지 않은 표준이병면적률(대조구에 대한 방제가, Control Value; C. V.) 대비표에 준하여 조사하였다. Botrytis cinerea isolated from cucumber gray mold disease was inoculated in potato agar medium (PEC) and incubated for 15 days under light dark at 25 ° C. to form spores. Spores formed on the medium were scraped and filtered to filter the spores, and the spore concentration was 1 × 10 6 / ml, followed by spray inoculation on one leaf cucumber. After treatment for 3 days at 20 ℃ in a wet room, the lesion area ratio of one leaf of the main leaf was examined. The incidence of the disease was investigated by comparing the area ratio of the lesions formed on the leaves of cucumbers, based on the control table (Control Value; CV), which was not treated with the standard treatment.
시험예 4: 토마토 역병(Tomato Late Blight, TLB)에 대한 시험Test Example 4: Test for Tomato Late Blight (TLB)
역병균(Phytophthora infestans)을 쥬스 한천(V-8 쥬스 200ml, CaCO34.5g, 한천 15g, 증류수 800ml) 배지에 올려놓고 20℃에서 16 시간 광처리와 8 시간 암처리하여 14일 배양한 후 포자를 수확하였다. 이때 플레이트에 살균 증류수를 넣고 흔들어서 유주자낭을 균총으로부터 떼어낸 후 4 겹 헝겊 조각을 사용하여 유주자낭만을 수확하였다. 수확한 유주자낭의 농도를 1×105개/ml로 조정하였고, 이 접종원을 토마토 유묘에 분무 접종하여 20℃ 습실상에서 1 일 동안 습실 처리한 후 20℃ 상대 습도 80% 이상의 항온 항습실로 옮겨 4일 동안 발병시킨 후 토마토 1 엽과 2 엽의 병반 면적율(%)을 조사하였다. 발병조사는 토마토의 잎에 형성된 병반 면적율을 조사하여 약제 처리하지 않은 표준 이병면적률 대비표에 준하여 조사하였다.After placing the phytophthora infestans on juice agar (200 ml of V-8 juice, 4.5 g of CaCO 3 , 15 g of agar, 800 ml of distilled water), and incubating for 14 days after 16 hours of light treatment and 8 hours of dark treatment at 20 ° C. Harvested. At this time, sterile distilled water was added to the plate and shaken to separate the zygote sac from the flora, and only 4 fold patches were harvested. The concentration of harvested saponiferous sac was adjusted to 1 × 10 5 / ml, and the inoculum was spray-inoculated on tomato seedlings and treated in a humidified room at 20 ° C. for 1 day, and then transferred to a constant temperature and humidity room with a relative humidity of 80% or higher at 20 ° C. 4 After the onset of the disease, the lesion area ratio (%) of one and two leaves of tomato was examined. The incidence was investigated by comparing the area ratio of lesions formed on the leaves of tomatoes according to the standard comparison table of the area of disease-free treatment.
시험예 5: 밀 붉은 녹병(Wheat Leaf Rust, WLR)에 대한 시험Test Example 5: Test for Wheat Leaf Rust (WLR)
병원균인 푹시니아 레콘디타(Puccinia recondita)는 실험실에서 식물체에 계대 배양하여 사용하였다. 균주의 계대 배양 및 약효 조사를 위하여 일회용 폿트(직경 6.5cm)에 15g 씩의 밀종자(은파밀)를 파종하여 온실에서 7 일간 재배한 1 엽기의 밀에 포자를 털어서 접종하였다. 접종한 1 엽기의 밀은 20℃의 습실 상에서 1 일간 습실 처리한 뒤에 상대 습도 70%이며 온도가 20℃인 항온 항습실로 옮겨 발병을 유도하고 접종 10일 후에 발병율을 조사하였다. 발병 조사는 밀의 잎에 형성된 병반 면적율을 조사하여 약제 처리하지 않은 표준이병면적률 대비표에 준하여 조사하였다. Puccinia recondita , a pathogen, was used by passage in plants in a laboratory. For subculture and pharmacological investigation of the strain, 15 g of wheat seeds (silver onions) were sown in disposable pots (6.5 cm in diameter) and spores were inoculated by shaking one leaf of wheat grown in a greenhouse for 7 days. After inoculation of the first leaf of the inoculated wheat at 20 ° C. for 1 day, it was transferred to a constant temperature and humidity room with a relative humidity of 70% and a temperature of 20 ° C. to induce the onset, and the incidence rate was examined 10 days after the inoculation. The incidence was investigated by comparing the area ratio of lesions formed on the leaves of wheat, based on the standard area ratio of untreated drugs.
시험예 6: 보리흰가루병(Barley Powdery Mildew, BPM)에 대한 시험Test Example 6: Test for Barley Powdery Mildew (BPM)
병원균인 에리시프 그라미니스(Erysiphe graminis)는 실험실에서 식물체에 계대배양하여 사용하였다. 균주의 계대 배양 및 약효 조사를 위하여 일회용 폿트(직경 6.5cm)에 15g 씩의 보리종자(동보리 1호)를 파종하여 온실(25+5℃)에서 7 일간 재배한 1 엽기의 보리에 흰가루병 포자를 털어서 접종하였다. 접종한 보리를 상대 습도 50%이며 온도가 22-24℃인 항온 항습실로 옮겨 7일간 발병을 유도한 뒤 발병 면적률을 조사하였다. 발병조사는 보리의 잎에 형성된 병반 면적율을 조사하여 약제 처리하지 않은 표준이병면적률 대비표에 준하여 조사하였다.The pathogen Erysiphe graminis was used for passage in plants in the laboratory. For seeding culture and investigation of medicinal effects, powdery spores were sprayed on barley of one leafy season, which was seeded with 15g of barley seeds (East barley No. 1) in disposable pots (6.5cm in diameter) and grown in greenhouse (25 + 5 ℃) for 7 days. Was inoculated by shaking. The inoculated barley was transferred to a constant temperature and humidity room with a relative humidity of 50% and a temperature of 22-24 ° C. to induce the disease for 7 days, and then the area of disease was investigated. The incidence was investigated by comparing the area ratio of lesions formed on barley leaves according to the standard area ratio of non-medical treatment.
상기의 시험예 1 내지 6에서 1 차 시험 농도 250 ppm에서 90% 이상의 방제가를 나타낸 화합물들은 2 차 시험 농도 50ppm에서 살균활성을 검정하였으며, 2차 시험 농도에서 90% 이상의 방제가를 나타낸 화합물들을 대상으로 보다 저농도인 10 ppm 및 2 ppm 농도에서 살균활성을 검정한 결과를 종합하여 그 결과를 하기 표 7a 내지 7e에 나타내었다.Compounds showing 90% or more control value at 250 ppm of the first test concentration in Test Examples 1 to 6 were tested for bactericidal activity at 50 ppm of the second test concentration, and compounds having a control value of 90% or more at the second test concentration were tested. The results of assaying bactericidal activity at lower concentrations of 10 ppm and 2 ppm as a subject are summarized and shown in Tables 7a to 7e.
표 7a 내지 7e의 결과에서 알 수 있는 바와 같이, 본 발명의 화합물은 오리브라이트 및 페나리몰에 비하여 표적 균주에 대한 방제 범위가 넓고 약효 역시 우수하고 바람직한 살균활성을 보여주고 있다. 특히 벼도열병, 벼잎집얼룩병, 밀녹병 및 보리흰가루병에 대하여는 50ppm의 농도에서도 탁월한 방제 효과를 나타내었다.As can be seen from the results of Tables 7a to 7e, the compounds of the present invention have a wider control range for the target strains than oribright and phenarimol, and also have excellent efficacy and desirable bactericidal activity. In particular, rice fever, rice leaf blotch, wheat rust disease and barley powdery mildew showed excellent control effect at the concentration of 50ppm.
상기 약효 시험 결과에서 알 수 있듯이, 본 발명에 따른 옥심기를 가교로 하는 불소화 프로페닐기가 치환된 신규의 프로페노익 에스테르 및 아미드 유도체들은 낮은 농도에서도 우수한 살균 활성을 나타내며 항균범위가 매우 넓다.As can be seen from the results of the efficacy test, the novel propenoic ester and amide derivatives substituted with the fluorinated propenyl group crosslinking the oxime group according to the present invention show excellent bactericidal activity even at low concentrations and have a wide antibacterial range.
Claims (5)
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| Application Number | Priority Date | Filing Date | Title |
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| KR1019990033724A KR100311196B1 (en) | 1999-08-16 | 1999-08-16 | Fluropropenyl-substituted propenoic ester and amide compound having oxime bridge, process for preparing same and antifungal composition comprising same |
| EP00952045A EP1204632B1 (en) | 1999-08-16 | 2000-08-16 | Fungicidal compounds having a fluorovinyl- or fluoropropenyl-oxyphenyloxime moiety and process for the preparation thereof |
| US10/049,412 US6552080B1 (en) | 1999-08-16 | 2000-08-16 | Fungicidal compounds having a fluorovinyl-or fluoropropenyl-oxyphenyloxime moiety and process for the preparation thereof |
| AU64807/00A AU753165B2 (en) | 1999-08-16 | 2000-08-16 | Fungicidal compounds having a fluorovinyl- or fluoropropenyl-oxyphenyloxime moiety and process for the preparation thereof |
| CA002380864A CA2380864C (en) | 1999-08-16 | 2000-08-16 | Fungicidal compounds having a fluorovinyl- or fluoropropenyl-oxyphenyloxime moiety and process for the preparation thereof |
| CNB008117403A CN1178897C (en) | 1999-08-16 | 2000-08-16 | Fungicidal compounds having fluorovinyl-or-fluoropropenyl-oxyphenyloxime moiety and process for prepn. thereof |
| PCT/KR2000/000906 WO2001012585A1 (en) | 1999-08-16 | 2000-08-16 | Fungicidal compounds having a fluorovinyl- or fluoropropenyl-oxyphenyloxime moiety and process for the preparation thereof |
| AT00952045T ATE309198T1 (en) | 1999-08-16 | 2000-08-16 | FUNGICIDES CONTAINING A FLUOROVINYL OR FLUOROPROPENYLOXYPHENYLOXIM UNIT AND A METHOD FOR THE PRODUCTION THEREOF. |
| JP2001516886A JP3739703B2 (en) | 1999-08-16 | 2000-08-16 | Bactericidal compound having fluorovinyl- or fluoropropenyl-oxyphenyloxime residue and process for producing the same |
| DE60023909T DE60023909T2 (en) | 1999-08-16 | 2000-08-16 | FUNGICIDES WITH A FLUOROVINYL OR FLUORO-PROPENYLOXYPHENYLOXIM UNIT AND A METHOD OF PREPARING THEM. |
| BRPI0013409-0A BR0013409B1 (en) | 1999-08-16 | 2000-08-16 | fungicidal compounds having a fluorovinyl or fluorpropenyl oxyphenyloxime moiety and process for preparing them. |
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| KR1019990033724A KR100311196B1 (en) | 1999-08-16 | 1999-08-16 | Fluropropenyl-substituted propenoic ester and amide compound having oxime bridge, process for preparing same and antifungal composition comprising same |
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| KR100379761B1 (en) * | 2000-11-23 | 2003-04-11 | 한국화학연구원 | New propenoic ester and amide compound having oxime side chain, process for preparing same and antifungal composition comprising same |
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| EP0307103A2 (en) * | 1987-09-09 | 1989-03-15 | Zeneca Limited | Fungicides |
| WO1996006072A1 (en) * | 1994-08-19 | 1996-02-29 | Ciba-Geigy Ag | Oxime ethers and their use as pesticides |
| US5723473A (en) * | 1992-10-14 | 1998-03-03 | Zeneca Limited | Propenoic acid derivatives useful as fungicides |
| WO1998056774A1 (en) * | 1997-06-09 | 1998-12-17 | Basf Aktiengesellschaft | Bisimino-substituted phenyl compounds and their use as pesticides |
| WO1999006379A1 (en) * | 1997-07-30 | 1999-02-11 | Basf Aktiengesellschaft | Bisimino-substituted phenyl compounds and their use as pesticides |
| KR100229440B1 (en) * | 1997-05-16 | 1999-11-01 | 김충섭 | Novel propenoic ester and amide derivatives having a fluorovinyl group |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0307103A2 (en) * | 1987-09-09 | 1989-03-15 | Zeneca Limited | Fungicides |
| US5723473A (en) * | 1992-10-14 | 1998-03-03 | Zeneca Limited | Propenoic acid derivatives useful as fungicides |
| WO1996006072A1 (en) * | 1994-08-19 | 1996-02-29 | Ciba-Geigy Ag | Oxime ethers and their use as pesticides |
| KR100229440B1 (en) * | 1997-05-16 | 1999-11-01 | 김충섭 | Novel propenoic ester and amide derivatives having a fluorovinyl group |
| WO1998056774A1 (en) * | 1997-06-09 | 1998-12-17 | Basf Aktiengesellschaft | Bisimino-substituted phenyl compounds and their use as pesticides |
| WO1999006379A1 (en) * | 1997-07-30 | 1999-02-11 | Basf Aktiengesellschaft | Bisimino-substituted phenyl compounds and their use as pesticides |
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| KR100379761B1 (en) * | 2000-11-23 | 2003-04-11 | 한국화학연구원 | New propenoic ester and amide compound having oxime side chain, process for preparing same and antifungal composition comprising same |
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