Title of Invention

"A PROCESS FOR THE PREPARATION OF A COMPOUND OF FORMULA (I-B)"

Abstract A fungicidal compound of formula (I) having a fluorovinye-or fluoropropenyl-oxypheny-loxime moiety and stereoisomers thereof are useful for protecting corps from fungal diseases: wherein, X is CH or N; Y is O or NH; R1 is hydrogen, C1-4 alkyl, or halogen-substituted C1-4 alkyl, R2 is a phenyl group optionally carrying one or more substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, methyienedioxy and halogen; or a naphthyl group; and R3 is hydrogen or CF3.
Full Text FUNGICIDAL COMPOUNDS HAVING A FLUOROVINYL- OR FLUOROPROPENYL-OXYPHENYLOXIME MOIETY AND PROCESS FOR THE PREPARATION THEREOF
Field of the Invention
The present invention relates to novel fungicidal compounds having a fluorownyl-or fluoropropenyl-oxyphenyloxime moiety, a process for preparing same and a fungicidal composition containing same as an active ingredient
Description of the Pnor Art
A number of fungicidal compounds have been in practical use to protect crops from various pathogenic fungi, and they may be classified into several groups according to their similar structural features However, the repetitive use of a fungicide o\ er a long period induces the appearance of new fungal strains resistant not only to the particular fungicide but also to related fungicides having common structural features For this reason, continuous efforts have been undertaken to develop novel fungicides
Such efforts have led to the development of new fungicides, e g , propenoic esters derived from strobilunn (US Patent No 4,994,495, WO 94/19331, US Patent No 5,003,101) and other propenoic ester fungicides disclosed in EP A 0 278 595 (Zeneca), EP A 0 782 982 (Novatis), WO 96/33164 (C1-ba-Geigy), WO 9603164 (Rhone-Poulenc Agro), WO 98/56774 (BASF), WO 99/06379 (BASF), WO 99/23066 (Agrevo UK), German Patent Nos 724,200 and 732,846 (both BASF), and British Patent No 22 893 (Agrevo UK) However, these propenoic ester derivatives still have the problem of limited fungicidal activity
Summary of the Invention
Accordingly, it is a primary object of the present invention to provide a novel compound having a high fungicidal activity against a wide spectrum of plant pathogenic fungi
It is another object of the present invention to provide a process for the preparation of said compound
It is a further object of the present invention to provide a fungicidal composition containing said compound
In accordance with one aspect of the present invention, there are provided a novel
compound of formula (I) and stereoisomers thereof Formula Removed)
X is CH or N,
Y is O or NH,
R1 is hydrogen, C1-4 alkyl, or halogen-substituted C1-4alkyl,
R is a phenyl group optionally carrying one or more substnuents selected from the
group consisting of C1-4 alkyl, C1-4 alkoxy, methylenedioxy and halogen, or a naphthyl
group,and
R3 is hydrogen or CF3
Detailed Description of the Invention
The structure of the compound of formula (I) of the present invention is characterized by the fluorovinyl- or fiuoropropenyl-oxyphenyloxime moiety, and depending on whether X is CH or N, it may also be classified as a propenoic acid derivative (X=CH) or as an lminophenylacetic acid derivative (X=N)
Among the compounds of the present invention, preferred are those wherein R1 is hydrogen or methyl, and R2 is phenyl group, or C1- or F-substituted phenyl group
The compound of formula (I) of the present invention may be prepared as shown m Reaction Scheme A
Reaction Scheme A
(Scheme Removed)
wherein, X, R1, R2 and R3 have the same meanings as defined in formula (I) above
In Reaction Scheme A, the compound of formula (I-a), 1 e, a compound of formula (I) wherein Y is O, may be prepared by the steps of (a) reacting a compound of formula (II) with an oxime derivative of formula (EI) in the presence of a base to obtain a compound of formula (TV), (b) debenzylating the compound of formula (IV) by hydrogenolysis m the presence of a Pd(C) catalyst to obtain a compound of formula (V-a), and (c) reacting the compound of formula (V-a) with a compound of formula (VI) in the presence of a base
The compound of formula (II) is inclusive of the compounds of formula (Il-a)
(Formula Removed)
(X=CH) and formula (Il-b) (X=N)
(Formula Removed)
The compound of formula (Il-a) may be prepared by estenfication, formylation, methylation and bromination of o-tolylacetic acid according to a conventional method (Yamada K et al, Tetrahedron Lett, 2745(1973), Vyas, G N et al, Oig Svn Coll 4, 836(1963), Kahr, A, Org Syn Coll, 5, 825(1973), Korean Unexamined Patent Publication Nos 98-83587 and 99-15785, and World Patent Publication No WO 99/07665), as shown in Reaction Scheme B
Reaction Scheme B
(Scheme Removed)
The compound of formula (Il-b) may be prepared by Gngnard reaction, oxalylation, condensation, methylation and bromination of o-bromotoluene according to a conventional method (Rambaud, M et al, Synthesis, 564(1988), Korean Unexamined Patent Publication Nos 98-83587 and 99-15785, and World Patent Publication No WO 99/07665), as shown in Reaction Scheme C
Reaction Scheme C
(Scheme Removed)
The compound of formula (III), on the other hand, represents, among others, the compounds of formula (Ill-a) (R'=H), formula (III-b) (R'=CHi) and formula (III-c) (R'= CF3)
(Formula Removed)
The compounds of formulas (Ill-a), (III-b) and (III-c) may be prepared by the steps of benzylation and condensation of 3-hydroxybenzaldehyde, 3-hydroxyacetophenone and 3-hydroxy-2'2'2'-tnfluoroacetophenone respectively in accordance with a conventional method (Kuhn, R et al, Chem Ber 90, 203(1957), Fletcher, H G et al, Methods Carbohydr Chem , //, 166(1963) Freedman, H H et al Tetrahedron Lett, 3251(1975), Lichtenhaler, F W, et al, Tetrahedron Leu , 1425(1980), and Sugg, E E , et al, J Org Chem , 50, 5032(1985)), as shown in Reaction Scheme D
Reaction Scheme D
(Scheme Removed)
wherein, R1 has the same meanings as defined in formula (I) above
In the reaction to prepare the compound of formula (IV), the compound of formula (II) and the compound of formula (III) may be used in equimolar amounts and the base may be used in one or two equivalent amounts The base may be an inorganic base, e g, sodium hydride, potassium /-butoxide, sodium carbonate or potassium carbonate, or an organic base, e g , tnethyl amine or pyridine The solvent which may be used in the reaction includes acetone, methyl ethyl ketone, benzene, toluene tetrahydrofuran, acetonitnle, dichloromethane or dimethyl formamide, and the reaction may be conducted at a temperature ranging from room temperature to 100 °C The progress of the reaction is conveniently followed by measuring the disappearance of the compound of formula (II) with thin layer chromatography (TLC)
Examples of the compound of formula (IV) include the compounds of formulas (IV-a) (X=CH, R'=H), (IV-b) (X=CH, R'=CH3), (IV-C) (X=CH, R'=CF3), (IV-d) (X=N, R'=H), (IV-e) (X=N, R'=CH3) and (IV-f) (X=N, R1=CF3), depending on the starting materials used, i e , depending on any one of the reactions of the compound of formula (Il-a) or (Il-b) with the compound of formula (Ill-a), (Ill-b) or (III-c)
(Formula Removed)
Subsequently, the compound of formula (IV) is debenzylated b\ hydrogenolysis to obtain a phenolic ester compound of formula (V-a)
(Formula Removed)
wherein, X and R1 has the same meanings as defined previously
Examples of the compound of formula (V-a) include the compounds of formulas (V-a-1) (X=CH, R'=H), (V-a-2) (X=CH, R'=CH3), (V-a-3) (X=CH, R'=CF3), (V-a-4) (X=N, R'=H), (V-a-5) (X=N, R]=CH3) and (V-a-6) (X=N, R'=CF3), which correspond to the compounds of formulas (IV-a) to (IV-f), respectively
(Formula Removed)
On the other hand, the compound of formula (VI) is inclusive of a compound of formula (Vl-a), 1 e , the compound of formula (VI) wherein R1 is H, and a compound of formula (Vl-b), 1 e , the compound of formula (I) wherein R3 is CF3
(Formula Removed)
The compound of formula (Vl-a) may be prepared by a Gngnard reaction reduction, halogenation and dehalogenation of a halide of R2 according to a conventional method (Herkes, F E et al, J Org Chem, 32, 1311(1967), and Nemeth, G et al, J fluorine Chem , 76, 91(1996)), as shown in Reaction Scheme E
(Scheme Removed)
wherein, R2 has the same meaning as defined in formula (I) above, and Z represents CI or F
Further, a compound of formula (Vl-b) may be prepared by a Gngnard reaction and Wittig reaction of a halide of R2 according to a conventional method (Herkes, F E et al, J Org Chem, 32, 1311(1967), and Wheatman GA et al, J Org Chem, 48, 917(1983)), as shown in Reaction Scheme F
Reaction Scheme F
(Scheme Removed)
wherein, R" and Z have the same meanings as above
In the step to prepare the compound of formula (I-a) of the present invention by reacting the compound of formula (V-a) with a compound of formula (VI) in the presence of a base, the compounds of formulas (V-a) and (VI) may be used in equimolar amounts and the base may be used in one to two equivalent amounts The base may be an inorganic base, e g, sodium hydride, potassium r-butoxide, sodium carbonate or potassium carbonate, or an organic base, e g, tnethyl amine or pyridine The solvent, which may be used in the reaction, is benzene toluene tetrahydrofuran, acetomtnle, dichloromethane or dimethyl formamide, and the reaction temperature m the range of room temperature to 100 °C
In the preparation of the compound of formula (I-b) by reacting the phenolic ester compound of formula (V-a) with methylamme to obtain a phenolic amide compound of formula (V-b), in a conventional manner, and then reacting the compound of formula (V-b) with a compound of formula (VI) in the presence of a base, methylamme may be preferably employed in an excess amount than the phenolic ester compound used The above reaction may be conducted in the presence of an alcohol (e g , methanol), acetomtnle, dichloromethane and dimethyl formamide, at a temperature ranging from room temperature to the boiling point of the solvent used
Examples of the compound of formula (V-b) are the compounds of formulas (V-b-1) (X=CH, R'=H), (V-b-2) (X=CH, R'=CH3), (V-b-3) (X=CH, R'=CF,), (V-b-4) (X=N, R'=H), (V-b-5) (X=N, R'=CH3) and (V-b-6) (X=N, R'=CF3), which correspond to the compounds of formulas (TV-a) to (IV-f), respectively
(Formula Removed)
On the other hand, the compound of formula (I-a) may be prepared, as shown in the above Reaction Scheme A, by reacting a compound of formula (II) with a compound of formula (VII) in the presence of a base At this time, the compound of formula (II) and the compound of formula (VII) may be used in equimolar amounts and the base may be used in one or two equivalent amounts The base may be an inorganic base, e g , sodium hydride, potassium /-butoxide, sodium carbonate or potassium carbonate, or an organic base, e g, tnethylamme or pyridine The solvent which may be used in the reaction includes acetone, methyl ethyl ketone, benzene, toluene, tetxahydrofuran, acetonitnle, dichloromethane or dimethyl formamide, and the reaction may be conducted at a temperature ranging from room temperature to 100 °C The progress of the reaction is conveniently followed by measuring the disappearance of the compound of formula (II) with thin layer chromatography (TLC)
Further, the compound of formula (I-b) may be obtained by reacting the compound of formula (I-a) with methylamme in a conventional manner
The compound of formula (VII) may be prepared by reaction of 3-hydroxybenzaldehyde, 3-hydroxyacetophenone or 3-hydroxy-2'2'2,-tnfluoroaceto-phenone with a compound of formula (VI) to obtain a compound of formula (VIII) and condensation of the compound of formula (VIII) with hydroxylamine according to a conventional method (Lichtenhaler, F W, et al, Tetrahedron Lett, 1425(1980), and Sugg, E E , et al, J Org Chem , 50, 5032(1985)), as shown in Reaction Scheme G
Reaction Scheme G
(Scheme Removed)
wherein, R1, R2 and R3 have the same meanings as defined in formula (I) The compound of formula (VII) is inclusive of a compound of formula (Vll-a), i e the compound of formula (VII) wherein R3 is H, and a compound of formula (Vll-b), 1 e the compound of formula (VII) wherein R3 is CFj, which correspond to the compounds of formulas (Vl-a) and (Vl-b) used as a starting material, respectively
(Formula Removed)
The compound of formula (I) of the present invention has three double bonds, and when one ignores the double bond of the bridging oxime group, there exist four stereoisomers thereof, which, according to the terminology defined in the Cahn-Ingold-Prelog system (J March, Advanced Organic Chemistry, 3rd Ed Wiley-Interscience), may be expressed as (E,E), (E Z), (Z,E) and (Z I) isomeis which are included within the scope of the present invention
(when R3 is H, (E,Z) isomer, and when R3 is CF3, (E,E) isomer)
(Formula Removed) (when R3 is H, (E,E) isomer, and when R3 is CF3, (E,Z) isomer)
(Formula Removed)
(when R3 is H, (Z,Z) isomer, and when R3 is CF3, (2 E) isomer)
(Formula Removed)
(when R3 is H, (Z E) isomer, and when R3 is CF3, (Z Z) isomer) wherein, X, Y, R1, R2 and R3 have the same meanings as defined above
In case a mixture of the E and Z isomers of the compound of formula (II) is used in the reaction shown in Reaction Scheme A, the compound of the present invention is obtained as a mixture of the above four isomers wherein the (E,E ) and (E Z) isomers predominate with minor amounts of the (Z,E) and (Z,Z) isomers
However, in case only the E isomer of the compound of formula (II-a-4) or (II-b-4) is used, the compound of formula (I) of the present invention is obtained as a mixture of the (E E) and (E,Z) isomers, as is confirmed by ' H-NMR or 19F-NMR analysis
According to the 1H-NMR analysis (reference compound, TMS) of the compound of formula (I) of the present invention wherein R3 is hydrogen, a hydrogen of vinyl group of (E,E) isomer is shown as a doublet having a coupling constant of 5 to 6 Hz at 5 5 to 5 8 ppm, while that of (E,Z) isomer is represented as a doublet having a coupling constant of 30 Hz at 5 0 to 5 4 ppm The ratio of the (E E) isomer to (E Z) isomer is about 2 1 which may be calculated from integration on the 1H-NMR spectroscopy This result can be confirmed by the 19F-NMR analysis The 19F-NMR analysis of the compound (I) of the present invention wherein R3 is hydrogen, the fluorine substituent on the vinyl group of the (E E) isomer is shown as a doublet having a coupling constant of 5 5 Hz at -83 3 ppm, while that of the (E,Z) isomer is represented by a doublet having a coupling constant of 28 6 Hz at -83 1 ppm, and, the (E,E) to (E Z) isomer ratio is also confirmed to be about 2 1 from integration on the ,9F-NMR spectroscopy
According to the 19F-NMR analysis data of the compound of formula (I) of the present invention wherein R3 is CF3, the vinyl fluorine and the fluorine of CF3 of the
(E E) isomer are, respectively, a quartet having a coupling constant of 12 2 Hz at -75 9 ppm and a doublet having a coupling constant of 12 3 Hz at -58 7 ppm while those of the (E Z) isomer are, respectively, a quartet having a coupling constant of 23 9 Hz at -76 3 ppm and a doublet having a coupling constant of 24 7 Hz at -58 5 ppm The (E E) to (E Z) isomer ratio is about 1 2 based on the integration of fluorine peaks
The compound of the present invention has a broad spectrum of fungicidal activity against various plant pathogenic fungus, e g Pvi iculana oi-vzae Carvara KA301 which causes Rice Blast, Rhizoctoma solam AG-1 which causes Rice Sheath Blight, Botryhs cinerae which causes Cucumber Gray Mold Rot, Phytophthoi a infestans which causes Tomato Late Blight, Puccima recondita which causes Wheat Leaf Rust and Erysiphe gramims which causes Barley Powdery Mildew
Accordingly, the present invention also includes within its scope fungicidal compositions comprising one or more of the compounds of formula (I) or stereoisomer thereof as an active ingredient, in association with fungicidally acceptable earners
The fungicidal compositions of the invention may be formulated in various forms such as an emulsion, aqueous dispersion, powder and granules which may contain conventional additives The compound of the formula (I) may be used in an amount of 10 to 90 % on the basis of the weight of an emulsion or aqueous dispersion, and 0 1 to 10% on the basis of the weight of granules
Fungicidally acceptable earner that may be used in the present invention is a liquid earner, e g , water, an alcohol(ethanol, ethylene glycol, glycenne), ketone(acetone, methylethylketone), ether(dioxane, tetrahydrofuran, cellosolve), aliphatic hydrocarbon(gasohne, Kerosene), halogenated hydrocarbon(chloroform carbon tetrachlonde), amide(dimethylformamide) ester(ethyl acetate butyl acetate fattv glycenne ester) and acetonitnle, and a solid earner, e g , mineral particle(Kaohne clay, bentonite, dolomite, talc, silica, sand) and vegetable powder(shrubs)
The additive that may be used in the fungicidal composition of the present invention includes an emulsifier, adhesive dispersion agent or permeating agent e g nomonic, anionic or cationic interface active agent(fatty acid sodium salt, polyoxy alkvl ester, alkyl sulfonate ester) Further, an agrochemically active ingredient eg an insecticide, herbicide, plant growth regulator, germicide, and fertilizer, may be added in the composition of the present invention
The following Preparation and Examples are given for the purpose of illustration only and are not intended to limit the scope of the invention
Preparation 1 Preparation of methyl (2E)-3-mefhoxy-2-(2'-bromomethyl) phenyl-2-propenoate (compound of formula (II-a))
Step 1 Preparation of methyl o-tolylacetate
30 0 g (0 2 mol) of o-tolyl acetic acid was dissolved in 100 ml of methanol, 5 ml of concentrated sulfuric acid was added thereto and the resulting solution was stirred with heating for 6 to 12 hours The resulting solution was cooled and the solvent was removed under a reduced pressure to obtain a residue The residue was washed twice with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure The residue thus obtained was subjected to column chromatography using a mixture of/;-hexane and ethyl acetate (4 1) as an eluent to obtain 32 15 g (yield 98 %) of the title compound as a colorless liquid s
1H-NMR (CDC13, 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)
Step 2 Preparation of methyl 3-hydroxy-2-(2'-methyl)phenyl-2- propenoate
24 6 g (0 15 mol) of the compound obtained in Step 1 and 24 3 g (0 45 mol) of sodium methoxide were added to 300 ml of toluene, and 27 g (0 45 mol) of methylformate was added dropwise thereto over a period of 1 hour while cooling and stirring The resulting solution was stirred at room temperature for 12 hours and extracted twice or three times with water The combined aqueous layer was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate The organic layer was dried over magnesium sulfate and then the solvent was removed under a reduced pressure to obtain a residue The residue was subjected to column chromatography using a mixture of w-hexane and ethyl acetate (9 1) as an eluent to obtain 27 36 g (yield 95 %) of the title compound as a colorless liquid 1H-NMR (CDCh, 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)
Step 3 Preparation of methyl 3-methoxy-2-(2'-methyl)phenyl-2- propenoate
19 2 g (0 1 mol) of the compound obtained m Step 2, 15 12 g (0 12 mol) of dimethyl sulfate and 13 82 g (0 1 mol) of potassium carbonate were added to 200 ml of acetone, and the resulting solution was stirred for 12 hours with heating The solvent was removed under a reduced pressure and the residue was extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure to obtain a residue The residue was subjected to column chromatography using a mixture of w-hexane and ethyl acetate (4 1) as an eluent to obtain 17 1 g (yield 83 %) of the title compound having two isomers as a colorless
liquid
The title compound thus obtained was composed of 82% E isomer and 18% Z isomer

1H-NMR (CDCI3, 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)

1H-NMR(CDC13 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)
These isomers were separated and the E isomer was used in the following step
Step 4 Preparation of methyl (2E)-3-methoxy-2-(2'-bromomethyl)phenvl -2-propenoate 18 54 g (0 09 mol) of methyl (2 E)-3-methoxy-2-(2'-methyl)phenyl- 2-propenoate obtained in Step 3 and 16 0 g (0 09 mol) of N-bromosuccinimide were added to 100 ml of carbon tetrachloride Then, 0 16 g (1 mmol) of 2,2'-azo-bis-isobutyronitnle was added thereto, and the resulting solution was stirred for 12 hours with heating The resultant solution was cooled and filtered to remove succimmide The solvent was removed under a reduced pressure and an oily residue thus obtained was subjected to column chromatography using a mixture of «-hexane and ethyl acetate (4 1) as an eluent to obtain 21 73 g (yield 85 %) of the title compound as a colorless solid Melting Point 64-65 °C
1H -NMR (CDCI3, 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)
Preparation 2 Preparation of methyl (2 E)2-methoxyimino-2-(2'-bromomethyl)phenylacetate (compound of formula (II-b))
Step 1 Preparation of methyl 2-methylbenzoylformate
5 1 g (0 21 mol) of magnesium was placed in 300 ml of dry ether and 34 18 g (0 2 mol) of 2-bromotoluene was added dropwise thereto under a nitrogen atmosphere to prepare a Gngnard reagent The Gngnard reagent solution was cooled to -78 "C and 23 6 g (0 2 mol) of dimethyl oxalate was added dropwise thereto The resulting solution was stirred for 30 minutes, mixed with crushed ice, acidified with 20% hydrochloric acid and then extracted with ether The organic layer was washed three
times with water, dried over magnesium sulfate, and the solvent was removed under a reduced pressure to obtain a residue The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9 1) as an eluent to obtain 24 2 g (yield 68 %) of the title compound as a colorless liquid 1H -NMR (CDC13 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)
Step 2 Preparation of methyl 2-methoxyimino-2-(2'-methyl)phenylacetate
8 35 g (0 1 mol) of O-methylhydroxylamine hydrochloride and 8 1 ml (0 1 mol) of
pyridine were added to 100 ml of methanol, and then, 17 8 g (0 1 mol) of the compound
obtained in Step 1 was added thereto The resulting solution was stirred for 12 hours
with heating and concentrated under a reduced pressure The resultant solution was
mixed with water and extracted with ethyl acetate The organic layer was dried over
magnesium sulfate and the solvent was removed under a reduced pressure to obtain a
residue The residue was subjected to column chromatography using a mixture of
/i-hexane and ethyl acetate (4 1) as an eluent to obtain 19 04 g (yield 92 %) of the title
compound as a colorless liquid
The title compound thus obtained was composed of 50% Z isomer and 50% E isomer The Z isomer was a liquid and the E isomer was a solid obtained by recrystalhzation in n-hexane The structure of E isomer was identified by X-ray crystallography

lH -NMR (CDCI3, 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)

mp 63-64 °C
1H -NMR (CDCI3, 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) The E isomer was employed m following step
Step 3 Preparation of methyl (2 E)-2-methoxyimino-2-(2'-bromomethyl) phenylacetate
9 0 g (0 0435 mol) of methyl (2 E)-2-methoxyimino-2-(2'-methyl)-phenyl acetate
obtained in Step 2 and 7 74 g (0 0435 mol) of N-bromosuccinimide were added to 50 ml
of carbon tetrachloride, and then, 0 16 g (1 mmol) of 2,2'-azo-bis- isobutyronitnle was
added thereto The resulting solution was stirred for 12 hours with heating, solvent was
removed under a reduced pressure and obtained an oily residue which was subjected to
silica gel column chromatography using a mixture ofn-hexane and ethyl acetate (4 1) as
an eluent to obtain 11 08 g (yield 90 %) of the title compound as a colorless liquid
1H -NMR (CDCL3 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)
Preparation 3 Preparation of 3-benzyloxybenzaldoxime (compound of formula (III-a))
Step 1 Preparation of 3-benzyloxybenzaldehyde
24 2 g (0 2 mol) of 3-hydroxybenzaldehyde and 25 32 g (0 2 mol) of benzyl chloride were placed in 500 ml of acetone and 21 2 g (0 2 mol) of sodium carbonate was added thereto The resulting solution was stirred for 12 to 24 hours with heating, cooled to room temperature The solvent was removed under a reduced pressure and the residue thus obtained was washed with water and the extracted with ethyl acetate twice The organic layer was dried and the solvent was removed under a reduced pressure to obtain a residue The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9 1) as an eluent to obtain 35 6 g (yield 84 %) of the title compound as a colorless liquid
lH -NMR (CDC13, 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)
Step 2 Preparation of 3-benzyloxybenzaldoxime
31 8 g (0 15 mol) of the compound obtained in Step 1 and 11 47 g (0 165 mol) of hydroxylamine hydrochloride were placed in 200 ml of methyl alcohol, and 13 35 ml (0 165 mol) of pyridine was added thereto The resulting solution was re fluxed for 1 hour, and then was mixed with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure to obtain a white-colored residue The residue was washed with 100 ml of n-hexane to obtain 30 3 g (yield 89 %) of the title compound mp 58-59 °C
1H -NMR (CDCI3, 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)
Preparations 4 and 5 Preparation of 3-benzyloxyphenylmethyloxime (compound of formula (III-b)) and 3-benzyloxyphenyltnfluoromethyloxime (compound of formula (III-c))
The procedure of Preparation 3 was repeated except that 3-hydroxyphenyl methyl ketone and 3-hydroxyphenyl tnfluoromethyl ketone were used in place of 3-hydroxybenzaldehyde, to obtain the title compounds
The analysis data of the compounds prepared in Preparations 3 to 5 are listed in Table 1

(Table Removed)
Preparation 6 Preparation of methyl (2iT)-3-methoxy-2-[2-(({3-
benzyloxyphenyl)imino)oxy)methylphenyl]-propenoate (compound of formula (IV-a))
5 7 g (0 02 mol) of methyl (2E>3-methoxy-2-(2'-
bromomethyl)phenyl-2-propenoate and 4 54 g (0 02 mol) of 3-benyloxybenzaldoxime prepared in preparation 3 were placed in 50 ml of acetone and 2 76 g (0 02 mol) of potassium carbonate was added thereto The resulting solution was refluxed for 24 hours and cooled to room temperature, and the solvent was removed under a reduced pressure The residue thus obtained was mixed with water and extracted with ethyl acetate with three times The organic layer was dried over magnesium sulfate and filtered The filtrate was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (4 1) as an eluent to obtain 5 86 g (yield 68 %) of the title compound as a brown liquid
1H -NMR (CDC13, 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(M\ 21), 205(39), 189(50), 145(100), 91(67)
Preparations 7 to 11 Preparation of the compounds of formulas (IV-b) to (IV-f) as intermediates
The procedure of Preparation 6 was repeated except that methyl (2E)-3-methoxy-2-(2'-bromomethyl)phenyl-2-propenoate obtained in Preparation 1 and methyl (2E)-2-methoxyimino-2-(2'-bromomethyl)phenylacetate obtained in Preparation 2 and the oxime compounds obtained in Preparations 3 to 5 to obtain the compounds of formulas (IV-b) to (IV-f) as intermediates
The analysis data of the compounds prepared in Preparations 6 to 11 are listed in Table 2
Table 2
(Table Removed)
Preparation 12 Preparation of methyl (2E)-3-methoxy-2-[2-(((3-
hydroxyphenyl)imino)oxy)methylphenyl]-propenoate (compound of formula (V-a-1))
5 17 g (0 012 mol) of methyl (2E)-3-methoxy-2-[2-(((3-benzyloxyphenyl)immo)oxy)methylphenyl]-propenoate was dissolved in 50 ml of methyl alcohol, and a catalytic amount (25 mg, 0 01 mmol) of 5% palladium on
activated carbon was added thereto The resulting mixture was reacted with stirring foi
6 hours under a hydrogen pressure in a hydrogenation reactor The reaction mixture
solution was filtered to remove the activated carbon components, and the solvent was
removed under a reduced pressure The residue thus obtained was subjected to column
chromatography using a mixture of /z-hexane and ethyl acetate (2 1) as an eluent to
obtain 3 64 g (yield 89 %) of the title compound as a brown liquid
1H -NMR (CDCl3, TMS) δ (ppm) 8 02(s, 1H), 7 54(s, 1H), 7 53-6 84(m, 8H), 5 18(s
2H), 6 48(b, 1H), 5 14(s, 2H), 3 78(s, 3H), 3 67(s, 3H)
MS (m/e) 341(M+, 41), 250(37), 189(57), 145(100) 103(20)
Preparations 13 to 17 Preparation of the compounds of formulas (V-a-2) to (V-a-6) as intermediates
The procedure of Preparation 12 was repeated using the intermediates obtained in Preparations 7 to 11 to obtain the phenolic ester compounds of formulas (V-a-2 to (V-a-6) as intermediates
The analysis data of the compounds prepared in Preparations 12 to 17 are listed in Table 3
Table 3
(Table Removed)
Preparation 18 Preparation of N-methyl (2E)-3-methoxy-2-[2-(((3-
hydroxyphenyl)imino)oxy)methylphenyl]-propenamide (compound of formula (V-b-1)) 3 41 g (0 01 mol) of methyl (2E)-3-methoxy-2-[2-(((3-hydroxyphenyl)immo)oxy)methylphenyl]-propenoate was dissolved in 50 ml of methyl alcohol, and 40 ml of 40% methylamme aqueous solution was added thereto The resulting solution was stirred for 12 hours, and the solvent was removed under a reduced pressure The residue thus obtained was extracted with ethyl acetate The organic layer was dried and the solvent was removed under a reduced pressure The residue thus obtained was subjected to column chromatography using a mixture of H-hexane and ethyl acetate (2 1) as an eluent to obtain 2 90 g (yield 85 %) of the title compound as a brown liquid
1H -NMR (CDC13, TMS) δ (ppm) 8 01(s, 1H), 7 55(s, 1H), 7 54-6 88m, 8H), 6 53(b, 1H), 6 34(b 1H), 5 142s, 2H), 3 81(s, 3H), 2 79(d, 3H) MS (m/e) 340(M+, 38), 188(100), 144(72)
Preparations 19 to 23 Preparation of the compounds of formulas (V-b-2) to (V-b-6)
The procedure of Preparation 18 was repeated using the intermediates obtained
in Preparations 13 to 17 to obtain the phenolic amide compounds of formulas (V-b-2 to
(V-b-6) as intermediates
The analysis data of the compounds prepared in Preparations 18 to 23 are listed
in Table 4 Table 4 (Table Removed)
Preparation 24 Preparation of 2,2-difluorostyrene (compound of formula (VI-a))
Step 1 Preparation of 2,2,2-tnfluoromethyl phenyl ketone
5 1 g of magnesium(0 21 mol) was placed in 300 ml of dry diethyl ether and 31 4 g of bromobenzene (0 2 mol) was added dropwise thereto under a nitrogen atmosphere to prepare a Gngnard reagent The Gngnard reagent solution was cooled to -78 °C and 28 4 g of ethyl tnfluoroacetate (0 2 mol) was added dropwise thereto The resulting solution was stirred for 1 hour, mixed with an crushed ice, acidified with a concentrated hydrochlonc acid and then extracted three times with diethyl ether The organic layer was dried over magnesium sulfate and the solvent was removed under a
reduced pressure to obtain a residue The residue was distilled at 64 to 65 "C/33 mmHg to obtain 24 74 g (yield 71%) of the title compound as a colorless oil 1H -NMR (CDC13, TMS) δ (ppm) 7 52-7 12(m, 5H) MS (m/e) 174(M+, 21), 105(100), 77(82), 69(54)
Step 2 Preparation of l-hydroxy-2,2,2-tnfluoroethylbenzene
12 2 g (0 07 mol) of compound obtained in Step 1 was dissolved in 150 ml of methanol and 1 32 g (0 035 mol) of sodium borohydnde was added dropwise thereto for 30 minutes The resulting solution was stirred at room temperature for 2 hours and the solvent was removed Ethyl acetate was added thereto and the resultant solution was washed three times with water The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure to obtain a residue The residue was was distilled at 50 to 51 °C/1 mmHg to obtain 12 07 g (yield 98%) of the title compound as a colorless liquid
1H -NMR (CDCI3, TMS) δ (ppm) 7 54-7 13(m, 5H), 4 87(q 1H), 4 29(brs, 1H) MS (m/e) 176(M+, 39), 107(26), 79(91)
Step 3 Preparation of l-chloro-2,2,2-tnfluoroethylbenzene
11 97 g (0 068 mol) of the compound obtained in Step 2 and 83 g (0 7 mol) of thionyl chlonde were added to 100 ml of toluene and the mixture was stirred with heating for 12 hours The resulting solution was cooled and washed with water The organic layer was dned over magnesium sulfate and the solvent was removed under a reduced pressure to obtain a residue The residue was subjected to silica gel column chromatography using «-hexane as an eluent to obtain 9 9 g (yield 72%) of the title compound as a colorless liquid
1H -NMR (CDCl3, TMS) δ (ppm) 7 62-7 15(m, 5H), 5 10(q, 1H) MS (m/e) 194(M\ 94), 125(100), 83(30), 44(81)
Step 4 Preparation of 2,2-difluorostyrene
9 7 g (0 05 mol) of the compound obtained in Step 3 was dissolved in 50 ml of dry tetrahydrofuran, and then, 3 27 g (0 05 mol) of activated zinc was added thereto The resulting solution was refluxed for 12 hours while stirring and heating The resulting solution was cooled and filtered to remove precipitated salts The soh ent was removed under a reduced pressure and the residue was distilled at 58 to 59 "C/49 mmHg to obtain 6 09 g (yield 87%) of the title compound as a colorless oil 1H -NMR (CDCI3, TMS) δ (ppm) 7 45-7 10(m, 5H), 5 20(dd, 1H, 7=26Hz, 7=4Hz) MS (m/e) 140(M+, 100), 120(26), 84(16), 44(32)
Preparations 25 to 40
The procedure of Preparation 24 was repeated to obtain various fluonnated vinyl compounds of formula (Vl-a) The 1H-NMR and MS analysis data of the compounds obtained in Preparations 24 to 40 are shown in the following Table 5
Table 5 Substituted 2,2-difluorostyrene

(Table Removed)
Preparation 41 Preparation of 2,2-difluoro-l-tnfluoromethylstyrene (compound of formula (VI-b))
26 2 g (0 1 mol) of tnphenylphosphine was dissolved in 100 ml of dry tetrahydrofuran and 25 2 g (0 12 mol) of dibromodifluoro- methane was added dropwise thereto under a nitrogen atmosphere at a temperature below 10 °C The resulting solution was stirred for 30 minutes and thereto was added 8 71 g (0 05 mol) of the compound obtained in Step 1 of Preparation 24 The resultant solution was refluxed with heating for 48 hours, cooled and distilled under a reduced pressure The obtained oil was redistilled at a temperature of 51 to 52 "C/44 mmHg to obtain 7 07 g (yield 68%) of the title compound as a colorless liquid 1H-NMR (CDC13, TMS) δ (ppm) 7 59-7 31(m, 5H) 3 79(s, 3H) MS (m/e) 208(M\ 48), 84(83), 43(100)
Preparations 42 to 59
The procedure of Preparation 41 was repeated using corresponding halides in place of 4-bromobenzene to obtain various compounds of formula (VI-b) The 'H -NMR and MS data of these compounds are listed in Table 6
Table 6 Substituted 2,2-difluoro-l-tnfluoromethylstyrene

(Table Removed)
Preparation 60 Preparation of l-[3-(l-fluoro-2-phenyl)ethenyloxy]phenylmethyl oxime (compound of formula (VII-a))
Step 1 Preparation of l-[3-(l-fluoro-2-phenyl)ethenyloxy]phenyl-2-ethanone
In a dried vessel, 68 g (0 5 mol) of 3-hydroxyacetophenone was added to 400 ml of methylethylketone and thereto was added 83 g of potassium carbonate (0 6 mol) The resulting solution was stirred for 30 mmutes and 70 g (0 5 mol) of 2,2-dif]uorostyrene obtained in Preparation 24 was added slowly thereto The resultant solution was stirred for 24 hours with heating and filtered to remove solids The filtrate was concentrated and the residue was washed with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure The residue was distilled at 188 to 190 C/l mmHg to obtain 118 5 g (yield 92%) of the title compound as a colorless liquid
1H-NMR(CDC13, TMS)δ (ppm) 7 77-7 15(m, 9H), 5 75(d 0 8H(E)), 5 38(d 0 2H(Z)), 2 59(s, 3H)
MS (m/e) 256(M\ 100), 165(27), 109(62), 91(32), 43(72)
Step 2 Preparation of 1 -[3-( 1 -fluoro-2-phenyl)-ethenyloxy]phenylrnethyloxime
76 8 g (0 3 mol) of the compound obtained m Step 1 above and 22 2 g (0 32 mol) of hydroxyldmine hydrochloride were added to 500 ml ot methanol, and thereto was added 25 9 ml (0 32 mol) of pyridine The resulting solution was stirred at room temperature for 30 minutes and concentrated to remove the solvent The residue was mixed with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure The residue was was subjected to silica gel column chromatography using a mixture of/?-hexane and ethyl acetate (4 1) as an eluent to obtain 76 4 g (yield 94%) of the title compound as a colorless liquid
1H-NMR(CDC13, TMS)δ (ppm) 8 26(brs, 1H), 7 46-7 16(m, 9H), 5 74(d, 0 8H(E)), 5 37(d, 0 2H(Z)), 2 29(s, 3H)
MS (m/e) 271(M+, 100), 118(42), 109(41), 90(22)
Preparation 61 Preparation of l-[3-(l 3,3,3-tetrafluoro-2-phenyl)-l-propenyloxy] phenvlmethyloxime (compound of formula (VII-b))
The procedure of Preparation 60 was repeated using 2,2-difluoro-l-tnfluoromethylstyrene obtained in Preparation 41, in place of 2,2-difluorostyrene, to obtain the title compound as a colorless liquid
1H-NMR(CDCl3, TMS)5 (ppm) 8 44(br s, 1H), 7 51-6 99(m, 9H), 2 25(s, 3H)

MS (m/e) 339(M\ 100), 186(37), 134(40), 117(26), 89(36)
Example 1 Preparation of methyl (2E)-3-methoxy-2-{2'-[[[3"-(1"-fluoro-2"'-phenyl-l"'-ethenyloxy)phenyl]imino]oxy]methylphenyl}propenoate (Compound 1)
341 mg (1 mmol) of the compound obtained in Preparation 12 was added to 10 ml of acetonitnle and 40 mg of sodium hydride (1 mmol) dispersed in mineral oil(60%) was added thereto under a nitrogen atmosphere The resulting solution was stirred for 30 minutes and 140 mg (1 mmol) of the compound obtained in Preparation 24 was added slowly thereto The resultant solution was stirred for 4 hours with heating mixed with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure The residue was subjected to silica gel column chromatography using a mixture of n-hexane and ethyl acetate (4 1) as an eluent to obtain 420 mg (yield 91%) of the title compound as a colorless liquid
1H-NMR(CDC13, TMS)δ (ppm) 8 04(s, 1H), 7 58(s, 1H), 7 50-7 08(m, 13H), 5 68(d, 1H), 5 09(s, 2H), 3 79(s, 3H), 3 65(s, 3H)
19F-NMR(CDC13, CFC13)δ (ppm) -83 066(d, IF, J=28 614Hz, Z isomer), -83 344(d, IF, J=5 55Hz, E -isomer) MS(m/e) 461(M+ 48), 205(33), 189(63), 145(100), 103(15)
Example 16 Preparation of N-methyl (2 E)3-methoxy-2-{2'-[[[3"-(1 "'-fluoro-2'"-phenyl-1"-ethenyloxy)phenyl]imino]oxy]methylphenyl }propenamide (Compound 16)
170 mg (0 5 mmol) of the compound obtained in Preparation 18 was added to 10 ml of acetonitnle and 40 mg of sodium hydride (1 mmol) dispersed in mineral oil (60%) was added thereto under a nitrogen atmosphere The resulting solution was stirred for 30 minutes and 70 mg (0 5 mmol) of the compound obtained in Preparation 24 was added slowly thereto The resultant solution was stirred for 4 hours with heating, mixed with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure The residue was subjected to silica gel column chromatography using a mixture of H-hexane and ethyl acetate (4 1) as an eluent to obtain 221 mg (yield 96%) of the title compound as a colorless liquid
1H-NMR (CDCl3, TMS)δ (ppm) 8 07(s, 1H), 7 61(s, 1H), 7 59-6 89(m, 13H), 5 71(d, 1H), 5 17(s, 2H), 4 14(br, 1H), 3 64(s, 3H), 2 96(d, 3H)
MS(m/e) 460(M\ 28), 188(100) 149(53)
Example 40 Preparation of methyl (2 E)-3-methoxy-2-{2'-[[[3"-(1 "'-fluoro-2"'-phenyl-1 '"-ethenyloxy)phenyl]methylimino]oxy]methylphenyl} propenoat e (Compound 40)
28 4 g (0 1 mol) of methyl (2E)-3-methoxy-2-(2'-bromomethyl) phenyl-2-propenoate obtained m Preparation 1 (the compound of formula (II-a)) and 27 1 g (0 1 mol) of the compound obtained in Preparation 60 (the compound of formula (VII-a)) were added to 200 ml of acetone, and thereto was added 13 8 g (0 1 mol) of potassium carbonate The resulting solution was stirred for 24 hours with heating and cooled to room temperature The solvent was removed under a reduced pressure, and the residue was mixed with water and extracted three times with 50 ml of ethyl acetate The organic layer was dried over magnesium sulfate and filtered The filtrate was concentrated and the residue was subjected to silica gel column chromatography using a mixture of «-hexane and ethyl acetate (9 1) as an eluent to obtain 33 8 g (yield 71%) of the title compound as a colorless liquid
1H-NMR(CDC13, TMS)δ (ppm) 7 48(s, 1H), 7 42-6 87(m, 13H), 5 67(d, 1H), 5 20(s, 2H), 3 78(s, 3H), 3 65(s, 3H), 2 24(s, 3H)
MS (m/e) 475(M+, 11), 205(35), 189(17), 145(100), 109(31)
Example 64 Preparation of methyl (2 E)-2-methoxyimino-2-{2'-[[[3"-(1"-fluoro-2"'-phenyl-1"-ethenyloxy)phenyl]methylimino]oxy]methylphenylacetate (Compound 64)
The procedure of Example 40 was repeated using methyl (2E)-2-methoxyimino-2-(2'-bromomethyl)phenylacetate obtained in Preparation 2 in place of the compound obtained in Preparation 1, to obtain the title compound as a colorless liquid
lH-NMR(CDCl3, TMS)δ (ppm) 7 49-7 16(m, 13H), 5 73(d 1H), 5 15(s 2H) 4 04(s, 3H), 3 82(s, 3H), 2 21(s, 3H)
MS (m/e) 476(M+, 11), 131(68), 116(100), 59(44)
Example 77 Preparation of N-methyl (2 E)-2-methoxyimino-2-{2'-[[[3"-(1'"-fluoro-2"'-phenyl-r"-ethenyloxy)phenyl]methyhmino]oxy]methylphenylacetamide (Compound 77)
The procedure of Preparation 18 was repeated using Ccompound 64 obtained in Example 64, in place of the propenoate compound, to obtain the title compound as a colorless liquid
1H-NMR(CDC13 TMS)δ (ppm) 7 47-7 15(m, 13H) 6 71(b, 1H), 5 70(d 1H) 5 13(s, 2H), 3 93(s, 3H), 2 84(s, 3H), 2 18(s, 3H)
MS (m/e) 475(M' 11), 132(50) 116(68), 58(100)
The procedure of Example 1 or 16 was repeated using corresponding phenolic ester compounds or phenolic amide comounds of formula (V) and fluonnated vinyl comounds of formula (Vl-a), or, alternatively, the procedure of Example 40, 64 or 77 was repeated using corresponding bromide compounds of formula (II) and olefin substituted oxime compounds of formula (VII-a), to obtain various compounds of formula (I) as listed in Table 7 (Table Removed)
Example 103 Preparation of methyl (2E)-3-methoxy-2-{2'-[[[3"-(l"-fluoro-3",,3",3",-trifluoro-2'"-phenyl- 1,-propenyloxy)phenyl]imino]oxy]methylphenyl}
propenoate (Compound 103)
341 mg (1 mmol) of the compound obtained in Preparation 12 was added to 10 ml of acetomtnle and 40 mg of sodium hydride (1 mmol) dispersed m mineral oil (60%) was added thereto under a nitrogen atmosphere The resulting solution was stirred for 30 mmutes and 208 mg (1 mmol) of the compound obtained in Preparation 41 was added slowly thereto The resultant solution was stirred for 4 hours with heating, mixed with water and extracted with ethyl acetate The organic layer was dned over magnesium sulfate and the solvent was removed under a reduced pressure The residue was subjected to silica gel column chromatography using a mixture of n-hexane and ethyl acetate (4 1) as an eluent to obtain 470 mg (yield 91%) of the title compound as a colorless liquid
1H-NMR(CDC13, TMS)δ (ppm) 8 01 (s, IH), 7 59(s, IH), 7 58-6 92(m, 13H), 5 18(s, 2H),3 78(s,3H),3 61(s,3H)
,9F-NMR(CDC13, CFC13)δ (ppm) -75 916(q, 3F, J=l222Hz), -58 714(d IF J = 12 267Hz) E,E-isomer, -76 313(q, 3F, J=23 93Hz), -58 518(d, IF, J=24 676Hz) E Z-isomer MS(m/e) 529(M+, 18), 205(59), 189(75), 145(100), 131(25)
Example 120 Preparation of N-methyl (2E)-3-methoxy-2-{2'-[[[3"-(l,"-fluoro-3,",3"',3,"-tnfluoro-2",-phenyl-l'"-propenyloxy)phenyl]imino]oxy] methylphenyl}propenamide (Compound 120)
170 mg (0 5 mmol) of the compound obtained in Preparation 18 was added to 10 ml of acetomtnle and 40 mg of sodium hydride (1 mmol) dispersed in mineral oil (60%) was added thereto under a nitrogen atmosphere The resulting solution was stirred for 30 minutes and 104 mg (0 5 mmol) of the compound obtained in Preparation 41 was added slowly thereto The resultant solution was stirred for 2 hours at room temperature mixed with water and extracted with ethyl acetate The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure The residue was subjected to silica gel column chromatography using a mixture of H-hexane and ethyl acetate (4 1) as an eluent to obtain 243 mg (yield 92%) of the title compound as a colorless liquid
1H-NMR(CDC13, 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)
The procedure of Example 103 or 120 was repeated using corresponding phenolic ester compounds or phenolic amide comounds of formula (V) and fluonnated vinyl compounds of formula (Vl-b), or, alternatively, the procedure of Example 40, 64 or 77 was repeated using corresponding bromide compounds of formula (II) and the olefin substituted oxime compounds of formula (Vll-b), to obtain various compounds of formula (I), as listed m Table 8
(Table Removed)
Fungicidal Activity Test
To examine fungicidal activity of the compounds of the present invention each of the compounds listed in Table 3 and 4 was dissolved in 10% acetone to a concentration of 250 ppm, and Tween-20 was added thereto to a concentration of 250 or 500 ppm 50 ml of the resulting solution was sprayed on leaves of a host plant The plant was kept at room temperature for 24 hours to let the solvent evaporate, and then, a pathogenic fungus was inoculated thereonto The plant was held in a humidity chamber for 24 hours, transferred to an plant growth room kept at 20 to 27 °C and a relative humidity of 60 to 80% and kept to induce disease Subsequently, the lesion area (L A ) attacked by the pathogenic fungus was measured according to a method of Cho(Cho, KY, Search Report by Korea Research Institute of Chemical Technology(1989))" This procedure was repeated twice for each test 10% Acetone solution containing 250 ppm of Tween-20 was used as a control
The fungicidal activity of the compound of the present invention is repressed by a control value (C V ) calculated as,
(Formula Removed)
Test Example 1 Fungicidal activity against Rice Blast(RCB) disease
Pyricularia oryzae Carvara KA301 was inoculated on a nee bran agar medium (nee bran 20 g, dextrose 10 g, agar 15 g and distilled water 1 S, and cultured at 26 °C for 1 week The surface of the medium was scratched using a rubber pohshman to remove aenal mycelia, and cultured under a fluorescent light for 48 hours to form a spore Spores were suspended in stenhzed water at a concentration of 1x106 spore/ml The spore suspension was sprayed enough to soak the leaves of a RBC disease-sensitive Nakdong nee plant having 3 or 4 leaves The nee plant was held in a humidified dark room for 24 hours, transferred to an incubator kept at 24 to 28 °C and a relative humidity of more than 80% and kept for 5 days to induce RCB L A on a fully grown leaf appeanng underneath an uppermost leaf was measured to calculate an C V
Test Example 2 Fungicidal activity against Rice Sheath Bhght(RSB) disease
Rhizoctoma solam AG-1 was cultured on a PDA medium (potato 200 g, dextrose
20 g agar 20 g and distilled water 1 ? for 3 days and the agar disc(diameter 0 6 cm) was inoculated and cultured on sterilized wheat bran medium in a 1 L bottle at 26 to 28 °C for 7 days A mycelial mass was ground using a homogemzer, inoculated uniformly on soil of a pot wherein a Nakdong rice plant having 2 or 3 leaves and an height of 5 cm grew, and kept in humidity polyvinyl chamber for 5 days to induce RSB L A on a leaf sheath was measured to calculate an C V
Test Example 3 Fungicidal activity against Cucumber Gray Mold Rot (CGM) disease
Botrytis cinerae, which was isolated from cucumber infected thereby, was inoculated on a PDA agar medium and cultured under a 12L/12D cycle at 25 °C for 15 days to form spore The spores were scraped, filtered through a gauze and then suspended in potato dextrose liquid medium at a concentration of 1x106 spore/ml The spore suspension was sprayed on a cucumber plant having one leaf The cucumber plant was held in a humidified room at 20 °C for 3 days L A on a leaf was measured to calculate an C V
Test Example 4 Fungicidal activity on Tomato Late Bhght(TLB) disease
Phytophthora infestans was cultured on a juice agar medium(V-8 juice 200 ml, CaCO3 4 5 g, agar 15 g and distilled water 800 ml) under a 16L/8D cycle at 20 °C for 14 days Sterilized water was added thereto, the vessel was shaken to free zoospore sacs from the fungus mass and the zoospore sacs were collected using a four-layered gauze A zoospore sac suspension having a concentration of 1x105 spore/ml was sprayed on a young tomato plant The tomato plant was held in a humidified room at 20 °C for 24 hours, transferred to an incubator maintained at a temperature of 20 °C and a relative humidity of more than 80% for 4 days and cultured m to induce RBC L A on primary and secondary leaves was measured to calculate an C V
Test Example 5 Fungicidal activity against Wheat Leaf Rust(WLR) disease
Puccima recondita was subcultured on a wheat plant in a laboratory 15 g of wheat seeds was sowed in a pot diameter 6 5 cm) and cultured in a greenhouse for 7 days to obtain a wheat plant having only a primary leaf The wheat plant was inoculated with spores by shaking thereover another plant infected thereby The inoculated wheat plant was held in a humidified room at 20 °C for 24 hours, transferred to an incubator maintained at a temperature of 20 °C and a relative humidity of 70%

and cultured for 10 days to induce WLR L A on the primary leaf was measured to calculate an C V
Test Example 6 Fungicidal activity against Barley Powdery Mildew(BPM) disease
Ervsiphae graminis was subcultured on a wheat plant in a laboratory 15 g of barley seeds was sowed in a pot (diameter 6 5 cm) and cultured in a greenhouse for 7 days to obtain a barley plant having only a primary leaf The barley plant was inoculated with spores by shaking thereover another plant infected by BPM The inoculated barley plant was cultured in an incubator maintained at a temperature of 22 to 24 °C and a relative humidity of 50% for 7 days to induce BPM L A on the leaf was measured to calculate an C V
The results of subjecting the compounds of the present invention in Test example 1 to 6 at a concentration level of 250 ppm was more than 90% in most cases Accordingly, these compounds having a CV of more than 90% were subjected to another series of tests at reduced concentration levels of 50, 10 and 2 ppm The test results are shown in Table 9
Table 9 Fungicidal Activities (Table Removed)


!) a product of Japan, Shionogi 2) a product of U S A , Dow Elanco
As can be seen from Table 9, the compounds of the present invention have a broad fungicidal activity spectrum against the target fungi when compared with the control compounds such as ORIBRIGHT™ and FENARIMOL™ In particular the inventive compounds have excellent fungicidal activity against RCB, RSB WLR and BPM
While the invention has been described with respect to the specific embodiments, it should be recogmzed that various modifications and changes may be made by those skilled in the art to the invention which also fall within the scope of the invention as defined by the appended claims






We claim:
1. A process for the preparation of a compound of formula (I-b), which comprises (a) reacting the phenolic ester compound of formula (V-a) with methylamine to obtain a compound of formula (V-b) and (b) reacting the compound of formula (V-b) with the compound of formula (VI) in the presence of a base:
(Formula Removed)
Wherein,
X is CH or N; R1 is hydrogen, C1-4 alkyl, or halogen-substituted C1-4 alkyl, R2 is a phenyl group optionally carrying one or more substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, methylenedioxy and halogen; or a naphthyl group; and R3is hydrogen or CF 3.
2. A process for the preparation of a compound of formula (I-b) substantially as herein described in the foregoing description and the accompanying examples and tables.


Documents:

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in-pct-2002-00175-del-complete specification (granted).pdf

in-pct-2002-00175-del-correspondence-others.pdf

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in-pct-2002-00175-del-description (complete).pdf

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in-pct-2002-00175-del-form-19.pdf

in-pct-2002-00175-del-form-2.pdf

in-pct-2002-00175-del-form-3.pdf

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in-pct-2002-00175-del-petition-138.pdf


Patent Number 236029
Indian Patent Application Number IN/PCT/2002/00175/DEL
PG Journal Number 39/2009
Publication Date 25-Sep-2009
Grant Date 16-Sep-2009
Date of Filing 12-Feb-2002
Name of Patentee KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY
Applicant Address #100, JANG-DONG, YUSEONG-GU, DAEJEON 305-343, REPUBLIC OF KOREA.
Inventors:
# Inventor's Name Inventor's Address
1 CHOI, GYUNG-JA NARAE APT. 104-1005, #462-4, JEONMIN-DONG, YUSEONG-GU, DAEJEON 305-390, KOREA.
2 KIM, JIN-CHEOL KONGDONGKWANRI APT. 8-202, #431, DORYONG-DONG, YUSEONG-GU, DAEJEON 305-340, KOREA.
3 PARK, NO-KYUN KYUNGNAM APT. 111-302, #409, DOMA-2-DONG, SEO-GU, DAEJON 302-162, REPUBLIC OF KOREA.
4 PARK, CHWANG-SIEK #383-6, DORYONG-DONG, YUSEONG-GU, DAEJEON 305-340, KOREA.
5 KIM, BUM-TAE SAMSUNG APT. 15-806, #175-1, OHRYU-DONG, JUNG-GU, DAEJEON 301-120, REPUBLIC OF KOREA.
PCT International Classification Number A01N 37/38
PCT International Application Number PCT/KR00/00906
PCT International Filing date 2000-08-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 1999/33724 1999-08-16 Republic of Korea
2 1999/33722 1999-08-16 Republic of Korea