KR100229440B1 - Novel propenoic ester and amide derivatives having a fluorovinyl group - Google Patents

Abstract

The present invention relates to a novel propenoic ester and amide derivative having a fluorovinyl group of the general formula (I) below, which has strong bactericidal activity, low toxicity, and improved drug sustainability, and a bactericide composition containing the same.

[Formula 1]

(Wherein X represents CH or N, Y represents O or S, Z represents O or NH, R represents hydrogen, alkyl having 1-4 carbon atoms or phenyl substituted with alkoxy, phenoxy, halogen or It represents a naphthyl group.)

Description

Novel propenoic ester and amide derivatives with fluorovinyl groups

The present invention relates to novel propenoic ester and amide derivatives with fluorovinyl groups having bactericidal activity.

In spite of excellent disinfectant effect, currently used disinfectants have been developed and used in analogues of the same structure, causing the expression of resistance to the pesticides of the fungus.

As part of an ongoing effort to solve this problem, propenoic esters, a new type of fungicide, which is obtained from recent hyphae of basidiomycetes and has been structurally transformed from natural strobilurin, which has a high activity of penetrating and transitional bactericidal activity. Compounds have emerged. Such compounds are described, for example, in European Patents 472,300 and Gen. 4,994,495, WO 94/19331, European Patents 581,095, European Patents 422,597 and US Patents 5,003,101, Ciba-Gai -European Patent No. 460,575 and the like. However, the fungicides mentioned in the above patents are weaker than conventional drugs or have a wide antimicrobial range and the like, and there is room for improvement such as short duration of drugs.

The present inventors synthesized a new propenoic ester and amide compound incorporating a fluorovinyl group in order to develop a compound having a stronger bactericidal activity, a lower toxicity than a conventional fungicide, and an economical compound having improved drug sustainability.

Accordingly, an object of the present invention is to introduce a new structure by introducing a fluorovinyl group to the propenoic ester and amide derivatives, unlike the conventional method, the manufacturing process is simple and excellent sterilizing power, as well as the sterilization spectrum is wide, so that several kinds of fungi can be used simultaneously. It is to provide novel propenoic ester and amide derivatives that can be rescued.

It is also an object of the present invention to provide a fungicide composition comprising such novel propenoic ester and amide derivatives as active ingredients.

According to the present invention there is provided a propenoic ester and amide derivative containing a fluorovinyl group represented by the following general formula (I):

[Formula 1]

Wherein X represents CH or N, Y represents O or S, Z represents O or NH, and R represents hydrogen, alkyl of 1-4 carbons or phenyl or naph substituted with alkoxy, phenoxy, halogen It represents a tilt group.)

It is most preferable when X is CH or N, Z is oxygen, and R is phenyl substituted by Cl or F among the compound of the said general formula (I).

According to the present invention, the novel propenoic ester and amide derivative represented by the general formula (I) can be prepared by the method shown in Scheme 1 below.

Scheme 1

(Wherein X, Y, Z and R are each as defined above)

Specifically, the compound (I) of the present invention is a bromide of the general formula (IV):

[Formula 2]

(Wherein X, Y and Z are as defined above, respectively)

Is reacted with 3-hydroxyphenol (lesosinol) in the presence of a base to give a phenolic compound of formula (II):

[Formula 3]

(Wherein X, Y and Z are as defined above, respectively)

To prepare a vinyl fluoride compound of the general formula (III)

[Formula 4]

(Wherein R is as defined above, respectively)

It can be manufactured in high yield by reacting in the presence of a base.

The bromide of general formula (IV) used as a starting material in the present invention is preferably the following structural formula (IV-a) (X = CH, Y = O, depending on the element corresponding to X, Y, Z) Z = O), the following structural formula (IV-b) (X = N, Y = O, Z = O), the following structural formula (IV-c) (X = CH, Y = S, Z = O) do.

[Formula 5]

[Formula 6]

[Formula 7]

First, (2E) -methyl 3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate represented by the above structural formula (IV-a) is represented by the following well-known method. It can be synthesized from esterification and formylation, methylation, bromination from o-tolyl acetic acid as shown in Yanmda, K, et al. Tetrahedron Lett., 2745 (1973); Vyas, G. N. et al., Org. Syn. Coll. Vol 4, 836 (1963); And Kalir, A., Org. Syn. Coll. Vol. 5, 825 (1973).

[Bungungsik 2]

(2E) -Methyl 2-methoxyimino-2- (2'-bromomethyl) phenylacetate represented by the above formula (IV-b) may be obtained by a well-known method as shown in Scheme 3 below. -Can be synthesized from bromotoluene through oxal oxidation, condensation, and bromination reactions. Rambaud, M. et al., Synthesis, 564 (1988); Korean Patent No. 88673; And Korean Patent Application No. 94-5088 (PCT / KR95 / 00020)].

Scheme 3

(2E) -methyl 3-thiomethoxy-2- (2'-bromomethyl) phenyl-2-propenoate represented by the above structural formula (IV-c) may be prepared by the following well-known methods. As shown, it can be synthesized from methyl 3-hydroxy-2- (2'-methyl) phenyl-2-propenoate through sulfonylation, nucleophilic substitution reaction and bromination reaction. [Reference: Korean Patent Application No. 95 -37559].

Scheme 4

In addition, the phenolic compounds of the general formula (II) produced as intermediates in the present invention correspond to the compounds of the structural formulas (IV-a), (IV-b) and (IV-c), respectively, used as starting materials. , The following structural formula (II-a) (X = CH, Y = O, Z = O), the following structural formula (II-b) (X = N, Y = O, Z = O) and the following structural formula (II-c (X = CH, Y = S, Z = O).

[Formula 8]

[Formula 9]

[Formula 10]

The compounds of the formulas (II-a), (II-b) and (II-c) are each represented by the above-described methods (IV-a) and (), as shown in Scheme 1 above. It can be obtained in high yield by reacting the compounds of IV-b) and (IV-c) with 3-hydroxyphenol (resosocin) in the presence of a base. In the reaction, the amount of the compound of formula (IV) and 3-hydroxyphenol (resosocinol) is used in equimolar amounts, and the base is preferably used in 2 equivalents with respect to these compounds. The base that can be used may be an inorganic base such as sodium hydride, t-butoxylated, sodium carbonate, potassium carbonate, and organic bases such as triethylamine and pyridine. In addition, acetone, benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane, or dimethylformamide may be used as the solvent, and the reaction temperature is appropriately within room temperature to 100 ° C, and the end point of the reaction is the formula All of the compounds of (IV) are consumed and this time can be easily identified by thin layer chromatography (TLC).

The vinyl fluoride compound of the general formula (III), which is required for the preparation of the general formula (I), which is the target compound of the present invention, has a chlorine reaction, a reduction reaction, a halogenation, using a halide as a raw material, as shown in Scheme 5 , Dehalogenation, and the like can be synthesized via a known method. See Herkes, FE et al., J. Org. Chem., 32, 1311 (1967); And Nemeth, G. et al., J. Fluorine Chem., 76, 91 (1996)].

Scheme 5

(Wherein R is as defined above)

The phenolic compound of formula (II) and the fluorine-substituted vinyl compound of formula (III) prepared by the above-mentioned preparation methods are reacted in the presence of a base as shown in Scheme 1, to provide a target compound of the present invention. Phosphorus compounds of formula (I) can be prepared.

In the above reaction, the amount of the compound of the general formula (II) and the compound of the general formula (III) is equimolar, and it is preferable to use 1-2 equivalents of the base with respect to these compounds. At this time, benzene, toluene, tetrahydrofuran, acetonitrile, dichloromethane or dimethylformamide can be used as the solvent. Bases that can be used include inorganic bases such as sodium hydride and t-butoxylate and organic bases such as triethyl amine and pyridine. The temperature of the reaction is appropriate from room temperature to 100 ℃, the end time of the reaction is when the reaction is consumed, which can be easily confirmed by TLC.

The compound of the general formula (I), which is the target compound of the present invention, has a double bond in two places in the molecule, and thus, depending on what steric configuration of the substituent Y for the double bond, and also for fluorine and hydrogen for the double bond, Depending on whether it has a three-dimensional configuration, in theory, the trans, trans (E, E) isomers, trans, cis (E, Z) isomers, cis, of the following formulas (Ia), (Ib), (Ic) and (Id), respectively There may be four isomers of the trans (Z, E) and cis, cis (Z, Z) isomers:

[Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

Wherein X, Y, Z and R are the same as defined above, respectively.

In the preparation of the compound of formula (I), the trans, trans (E, E) isomer (Ia) is used when the isomer produced in the preparation of the bromide of formula (IV) is used as a raw material in a mixture without purification. ) And the trans, cis (E, Z) isomer (Ib) as the main product, and the cis, trans (Z, E) isomer (Ic) and the cis, cis (Z, Z) isomer (Id) as a by-product. Mixed products can be obtained.

However, in the present invention, among the compounds of the general formula (I), the compounds having X = CH, Y = O, Z = O are methyl 3-methoxy-2- (2'-methyl) phenyl-2- which is a synthetic intermediate. In the synthesis of propenoate (IV-4a) (see Scheme 2), only the trans isomers were isolated from the isomers produced and used in the following reaction, and in general formula (I) wherein X = N, Y = O, Z = O The compound is a solid phase isomer when the 2-methoxyimino-2- (2'-methyl) phenylacetate (IV-3b) is synthesized (see Scheme 3). When the structure was determined by X-ray crystallography, it was found to be a trans isomer, and only these isomers were separated and used in the next reaction. Among the compounds of Formula (I), the compounds having X = CH, Y = S, Z = O are synthetic intermediates. Isomers generated upon synthesis of methyl 3-thiomethoxy-2- (2'-methyl) phenyl-2-propenoate (IV-3c) (see Scheme 4) By obtaining the undetrans isomer as a main product and separating and purifying it for use in the next reaction, the final product of the present invention is the E, E-isomer (Ia) produced from the reaction between the trans isomer and the vinyl fluoride compound (III). ) And E, Z-isomers (Ib), obtained as a mixture of two isomers, which are determined by ¹ H-NMR analysis of the chemical shift of hydrogen substituted with vinyl groups and the coupling constant of hydrogen and fluorine (coup1ing). constant). That is, in the case of E, E-form (Ia), hydrogen substituted with a vinyl group is represented by a double line having a coupling constant of 5 to 6 Hz at a position of 5.5 to 5.8 ppm, and in the case of E, Z-form (Ib), Substituted hydrogen was found to appear as a doublet with a coupling constant of about 30 Hz at the 5.0 to 5.4 ppm position. On the other hand, the ratio of the E, E body (Ia) and the E, Z -body (Ib) is about 3.5: 1, which is calculated as the H integral value on the ¹ H NMR.

As a result, the compound of the general formula (I) prepared by the production method of the present invention is actually obtained as a mixture in which the E and E forms (I-a) are the main products and the E and Z forms (I-b) are by-products.

Furthermore, according to the present invention, propene amide derivatives in which Z is NH in formula (I) can be obtained by reacting propenoic esters in which Z is 0 in formula (I) with amines by conventional methods.

For example, the propenoic ester compound may be reacted with an alkyl amine such as methylamine in an alcohol such as methanol to synthesize a propene amide compound, with the amine being preferably used in excess of the ester compound. In addition, solvents that may be used at this time include acetonitrile, dichloromethane or dimethylformamide in addition to alcohols including methanol, and amines that may be used in 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.

On the other hand, the present invention provides a bactericidal composition comprising the novel propenoic ester and amide compound having the fluorovinyl group of the general formula (I) as an active ingredient. The composition according to the present invention may be used by first mixing one or more of the compounds of the general formula (I) with a suitable carrier and a diluent in the form of a suitable formulation, for example, an emulsion, a wetting agent, a powder, a granule, or the like. In this case, the content of the active ingredient is, for example, 10-90% by weight if the preparation is an emulsion or a hydrating agent, 0.1-10% by weight if the powder, and 1-30% by weight in the case of granulation. However, some changes are possible depending on the purpose of the preparation.

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, cellosolve, etc.). Etc.), aliphatic hydrocarbons (gasoline, kerosene, etc.), halogenated hydrocarbons (chloroform, carbon tetrachloride), 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.

In addition, the composition of the present invention may be used by mixing other kinds of agrochemically active ingredients, such as insecticides, herbicides, plant growth regulators, fungicides, etc., and if necessary, fertilizers and the like may be mixed together.

The preparation method of novel propenoic ester and amide derivatives having a fluorovinyl group of the above formula (I), which is the target compound of the present invention prepared by the above method, will be described in more detail with reference to the following preparation examples and examples. .

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.

Preparation Example 1 Preparation of (2E) -Methyl 3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate (IV-a)

First Step: Preparation of Methyl O-tolyl Acetate

o-tolylacetic acid (30.0 g, 0.2 mo1) was dissolved in methanol (100 ml) and concentrated sulfuric acid (5 ml) was added as the acid catalyst, and the resulting mixture was heated with stirring for 12 to 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 organics, 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 o-tolyl acetate as a colorless liquid compound. (Yield 98%).

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)

Second Step: Preparation of Methyl 3-hydroxy-2- (2'-methyl) phenyl-2-propenoate

Methyl 0-tolyl acetate (24.6 g, 0.15 mo1) obtained in the first step was mixed with sodium methoxylated (24.3 g, 0.45 mo1), toluene (300 ml) was added, and methyl formate (27 g, 0.45 mo1) was cooled. ) Was added 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 then 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%).

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), 2.21 (s, 3H )

MS (m / e): 192 (M ⁺ , 26), 160 (52), 132 (48), 84 (100)

Third Step: Preparation of Methyl 3-methoxy-2- (2'-methyl) phenyl-2-propenoate

Methyl 3-hydroxy-2- (2'-methyl) phenyl-2-propenoate (19.2 g, 0.1 mol) obtained in the second step was diluted with dimethyl sulfate (15.12 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, and the residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) to give methyl 3-methoxy-2- (2'-methyl) as a colorless liquid compound. 17.1 g of phenyl-2-propenoate was obtained (yield 83%).

The product was a mixture of two isomers, and as a result, the component ratio was 82% of E (trans) isomer and 18% of Z (cis) isomer (down spot), and E was obtained as the main product. It was used for the next step.

E spot (upper spot): colorless liquid compound, yield 82%

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)

Z spot (down spot): colorless liquid compound, yield 18%

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)

Fourth Step: Preparation of (2E) -Methyl 3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate (IV-a)

(2E) -methyl 3-methoxy-2- (2'-methyl) phenyl-2-propenoate (18.54 g, 0.09 mol) and N-bromosuccinimide (NBS) obtained by separation in the third step , 16.0 g, 0.09 mo1) 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, the succinimide was removed by filtration, and the oily product obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) to give a colorless solid. As a compound, 21.73 g of (2E) -methyl 3 methoxy-2- (2'-bromomethyl) phenyl-2-propenoate was obtained (yield 85%, melting point: 64-65 ° C).

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)

Preparation Example 2 Preparation of (2E) -Methyl 2-methoxyimino-2- (2'-bromomethyl) phenylacetate (IV-b)

First step: preparation of methyl o-methylbenzoylformate

O-bromotoluene (34.18 g, 0.2 mol) was slowly added while stirring and stirring the ether and magnesium (5.1 g, 0.21 mol) dried under a nitrogen stream to prepare a Greenian reagent. After confirming that magnesium and o-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, and then the solvent was removed under reduced pressure, purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 9: 1) to give methyl o-methylbenzoylfo as a colorless liquid compound. 24.2 g of mate was obtained (yield 68%)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.88-7.01 (m, 4H), 3.98 (s, 4H), 2.65 (s, 3H)

MS (m / e): 178 (M ⁺ , 21), 119 (100), 91 (71), 65 (37)

Second Step: Preparation of 2-methoxyimino-2- (2'-methyl) phenylacetate

O-methylhydroxylamine hydrochloride (8.35 g, 0.1 mol) and pyridine (8.1 ml 0.1 mol) were mixed with methyl alcohol (100 ml), followed by methyl o-methylbenzoylformate (17.8 g, 0 lmol) 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%).

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. Recrystallization with n-hexane and the structure of the product at the melting point of 63 to 64 ℃ X-ray crystallization method confirmed that it was E. In the subsequent reaction step, only E was used.

Z spot (upper spot): colorless liquid compound

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)

E spot (down spot): colorless solid compound

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)

Third Step: Preparation of (2E) -Methyl 2-methoxyimino-2- (2'-bromomethyl) phenylacetate (IV-b)

(2E) -methyl 2-methoxyimino-2- (2'-methyl) phenyl acetate (9.0g, 0.0435mol) and N-bromosuccinimide (NBS, 7.74g, obtained by separation in the second step) 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. 11.08 g of (2E) -methyl 2-methoxyimino-2- (2'-bromomethyl) phenyl acetate was obtained (yield 90%).

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)

Preparation Example 3: Preparation of (2E) -Methyl 3-thiomethoxy-2- (2'-bromomethyl) phenyl-2-propenoate (IV-c)

First step: Preparation of methyl 3-methanesulfonyloxy-2- (2'-methyl) phenyl-2-propenoate Methyl 3-hydroxy 2- (obtained in the second step of Preparation Example 1 under a nitrogen stream. 2'-methyl) phenyl-2-propenoate (17 g, 0.089 mol) was dissolved in dried ethyl acetate (400 ml) and triethylamine (14 ml, 0.1 mo1) was added. Methanesulfonyl chloride (7.74 ml, 0.1 mol) was added dropwise to the reaction solution at room temperature over 30 minutes, followed by stirring. After stirring for 1-3 hours, the reaction solution was washed 2-3 times with water and dried, and then the solvent was removed under reduced pressure, purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1), and methyl 3-methane. 21.34 g of sulfonyloxy-2- (2'-methyl) phenyl-2-propenoate was obtained as a colorless liquid compound (yield 88.8%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 8.01 (s, 1H), 7.49-7.01 (m, 4H), 3.81 (s, 3H), 3.09 (s, 3H), 2.23 (s, 3H )

MS (m / e): 270 (M ⁺ , 51), 174 (100), 159 (96), 103 (89)

Second Step: Preparation of Methyl 3-thiomethoxy-2- (2'-methyl) phenyl-2-propenoate

Sodium thiomethoxylated (4.9 g, 0.07 m) and methyl 3-methanesulfonyloxy-2- (2'-methyl) phenyl-2-propenoate (16.2 g, 0.06 mo1) obtained in the first step After mixing with methanol (150ml) was added and stirred at room temperature for 4 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 evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1) to give methyl 3-thiomethoxy-2- (2'-) as a colorless liquid compound. 10.3 g of methyl) phenyl-2-propenoate was obtained (yield 77.3%).

The product was a mixture of two isomers. As a result, the component ratio was 92% of the E spot (upper spot) and 8% of the Z spot (down spot), and E was obtained as the main product.

Upper spot: colorless liquid compound

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.85 (s, 1H), 7.38-6.91 (m, 4H), 3.75 (s, 3H), 2.35 (s, 3H), 2.16 (s, 3H )

MS (m / e): 222 (M ⁺ , 20), 175 (21), 147 (36), 115 (100)

Step 3: Preparation of (2E) -Methyl 3-thiomethoxy-2- (2'-bromomethyl) phenyl-2-propenoate (lV-c)

(2E) -methyl 3-thiomethoxy-2- (2'-methyl) phenyl-2-propenoate (10.2 g, 0.046mo1) and N-bromosuccinimide (Separated from the Second Step) NBS, 9.25 g, 0.052 mol) was mixed with carbon tetrachloride (150 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 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 = 9: 1) to give a colorless liquid compound. 8.58 g of (2E) -methyl 3-thiomethoxy-2- (2'-bromomethyl) phenyl-2-propenoate was obtained (yield 62.0%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.98 (s, 1H), 7.69-7.01 (m, 4H), 4.45 (s, 2H), 3.73 (s, 3H), 2.45 (s, 3H )

MS (m / e): 300 (M ⁺ , 14), 161 (100), 145 (30), 115 (79)

Preparation Example 4 Preparation of (2E) -Methyl 3-methoxy-2- [2 '-(3 "-hydroxy) phenoxymethyl] phenyl-2-propenoate (II-a)

(2E) -Methyl 3-methoxy-2- (2'-bromomethyl) phenyl-2-propenoate (IV-a) (5.7 g, 0.02 mol), 3-hydric, produced in Preparation Example 1 Roxyphenol (resosocinol) (2.2 g, 0.02 mo1) and potassium carbonate (2.76 g, 0.02 mol) were mixed with acetone (100 ml) and the reaction solution was heated to reflux for 24 hours. The solvent was removed 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 = 2: 1) to give 4.52 g of the title compound as a colorless liquid compound (yield 72%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.67 (s, 1H), 7.65-6.21 (m, 8H), 4.89 (s, 2H), 3.78 (s, 3H), 3.65 (s, 3H ), 2.50 (br. S, 1H)

MS (m / e): 314 (M ⁺ , 21), 205 (98), 174 (28), l45 (100)

Preparation Example 5: Preparation of (E) -Methyl 2-methoxyimino-2- [2 '-(3 "-hydroxy) phenoxy methyl] phenylacetate (II-b)

(E) -Methyl 3-methoxyimino-2- (2'-bromomethyl) phenylacetate (IV-b) (5.66 g, 0.02 mo1) produced in Preparation Example 2 was prepared as starting material. 4.92 g of the title compound was obtained as a colorless liquid compound by the same method as in Example 4 (yield 78%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.54-7.01 (m, 9H), 4.89 (s, 2H), 4.01 (s, 3H), 3.85 (s, 3H)

MS (m / e): 315 (M ⁺ , 28), 284 (51), 206 (86), 132 (100), 116 (89).

Preparation Example 6: Preparation of (2E) -Methyl 3-thiomethoxy-2- [2 '-(3 "-hydroxy) phenoxymethyl] phenyl-2-propenoate (II-c)

(2E) -Methyl 3-thiomethoxy-2- (2'-bromomethyl) phenyl-2-propenoate (IV-c) (6.0 g, 0.02 mo1) produced in Preparation Example 3 was started. By using the same method as in Preparation Example 4 to obtain 3.23 g of the title compound as a colorless liquid compound (yield 49%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.98 (s, 1H), 7.71-6.28 (m, 8H), 5.81 (br.s, 1H), 4.89 (s, 2H), 3 .78 (s, 3H), 2 .35 (s, 3H)

MS (m / e): 330 (M ⁺ , 51), 221 (77), 161 (100), 145 (22), 115 (54)

Preparation Example 7 Preparation of 2,2-Difluoro-4'-methoxystyrene (III)

First Step: Preparation of 2,2,2-trifluoromethyl-4'-methoxyphenylketone (III-1)

Nitrogen gas was passed through a dried container, magnesium (5.1 g, 0.21 mo1) and 300 m1 of dried ether were added thereto, and p-bromoanisole (37.4 g, 0.2 mo1) was slowly added dropwise to prepare a GREEN reagent. The reaction solution was added dropwise with ethyl trifluoroacetate (28.3 g, 0.2 mol) under cooling to -78 deg. 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 35.09 g of 2,2,2-trifluoromethyl-4'-methoxyphenylketone as a colorless oily product at 20-mmHg at 72-73 占 폚 (yield) 86%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.62-6.81 (m, 4H), 3.86 (s, 3H)

MS (m / e): 204 (M ⁺ , 56), 135 (100), 107 (86), 92 (66), 77 (92)

Second step; Preparation of 1-hydroxy-2,2,2-trifluoroethyl-4'-methoxybenzene (III-2) 2,2,2-trifluoromethyl-4'-methoxy produced in the first step Phenylketone (14.28g, 0.07mo1) was mixed with methanol (150ml) and then sodium borohydride (1.32g, 0.035mo1) was added dropwise over 30 minutes and stirred. After stirring the reaction solution at room temperature for 1-2 hours, the solvent was removed, ethyl acetate was added and washed 2-3 times with water. 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 1-hydroxy-2,2,2- as a colorless liquid compound. 14 g of trifluoroethyl-4'-methoxy benzene were obtained (yield 97%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.62-6.78 (m, 4H), 4.92 (q, 1H), 3.94 (br.s, 1H), 3 .86 (s, 3H)

MS (m / e): 206 (M ⁺ , 42), 191 (62), 137 (100), 107 (26), 69 (56)

Third Step: Preparation of 1-Chloro-2,2,2-trifluoroethyl-4'-methoxybenzene (IIl-3)

1-hydroxy-2,2,2-trifluoroethyl-4'-methoxybenzene (14g, 0.068mol) and thionyl chloride (50g, 0.7mo1) produced in the second step were dried toluene ( 100 ml) and the reaction solution was heated with stirring for 12 hours. After cooling the reaction solution and washing with water, the organic layer was dried and the solvent was removed under reduced pressure, purified by silica gel column chromatography (eluent: n-hexane) to give 1-chloro-2,2,2 as a colorless liquid compound. 12 g of -trifluoroethyl-4'-methoxybenzene was obtained (yield 79%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.62-6.81 (m, 4H), 5.01 (q, 1H), 3.86 (s, 3H)

MS (m / e): 224 (M ⁺ , 23), 189 (100), 158 (79), 120 (56), 69 (43)

Fourth Step: Preparation of 2,2-difluoro-4'-methoxystyrene (III)

1-chloro-2,2,2-trifluoroethyl-4'-methoxybenzene (11.2g, 0.05mol) produced in the third step was mixed with dried tetrahydrofuran (THF, 50m1) and then activated. Zinc (Zn, 3.27 g, 0.05 mo1) was added and the resultant mixture was heated to reflux for 12 hours with stirring. The reaction solution was cooled to remove the salt formed by filtration, and the oily product obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluent: n-hexane) to give 2,2-di as a colorless liquid compound. 6.8 g of fluoro-4'-methoxystyrene were obtained (yield 80%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.51-6.69 (m, 4H), 5.29 (dd, 1H, J = 26 Hz, J = 4 Hz), 3.86 (s, 3H)

MS (m / e): 170 (N ^+, 100), 155 (68), 127 (92), 84 (21)

Preparation Examples 8-20

The fluorinated vinyl compound (III) used in the present invention was prepared in a similar manner as described in Preparation Example 7, and the analysis results of each step intermediate and final product in the preparation thereof are shown in Table 1 below. It was.

TABLE 1a

TABLE 1b

TABLE 1c

TABLE 1d

Example 1 (2E) -Methyl 3-methoxy-2- [2 '-[3 "-(2"'-fluorostyryl) -2 "'-oxy] phenoxymethyl] phenyl-2-propeno Manufacture of Eight

(2E) -Methyl-3-methoxy-2- [2 '-(3' '-hydroxy) phenoxymethyl] phenyl-2-prop as obtained in Preparation Example 4 by passing nitrogen gas through the dried vessel. Phenoate (314 mg, 1 mmol) was mixed with acetonitrile (10 ml) and sodium hydride (40 mg, 1 mol, 60% mineral oil dispersion) was added. After the reaction solution was stirred for 30 minutes, 2,2-difluorostyrene (140 mg, 1 mmol) obtained in Preparation Example 7 was slowly added thereto, followed by heating with stirring for 2-4 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 400 mg of the title compound (compound 1) as a colorless liquid (yield 92%). .

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.68 (s, 1H), 7.62-6.62 (m, 13H), 5.68 (d, 1H), 4.98 (s, 2H), 3. 7 8 (s, 3H), 3.69 (s, 3H)

MS (m / e): 434 (M ⁺ , 13), 205 (87), 145 (100)

Example 2 (2E) -N-methyl 3-methoxy-2- [2 '-[3 "-(2"'-fluorostyryl) -2 "'-oxy] phenoxymethyl] phenyl-2- Preparation of Propeneamide

(2E) -methyl 3-methoxy-2- [2 '-[3' '-(2 "'-fluorostyryl) -2w-oxy] phenoxymethyl] phenyl-2-prop obtained in Example 1 above Phenoate (2171 mg, 0.5 mmol) was mixed with methanol (5 ml), and methyl amine (2 ml, 40% aqueous solution) was added, the solvent was removed under reduced pressure for 12 hours, and extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) to obtain 206 mg of the title compound (compound 2) as a colorless liquid (yield 95%).

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 8.12 (br, 1H), 7.62-6.58 (m, 14H), 5.62 (d, 1H), 4.98 (s, 2H), 3. 6 9 ( s, 3H), 2.78 (d, 3H)

MS (m / e): 433 (M ⁺ , 6), 204 (41), 144 (100), 103 (24)

Examples 3 to 44

The preparations were carried out similarly to those described in Examples 1 and 2 using the compounds prepared in 4 to 20 to obtain compounds (compounds 3 to 44) as shown in Table 2 below.

TABLE 2a

TABLE 2b

TABLE 2c

Table 2d

TABLE 2e

[Efficacy test]

In order to investigate the preventive effect of the plant pathogens of the compound (I) of the present invention, after dissolving the compound of the present invention in a 10% acetone solution, 50 ml of foliar spray was applied to various host plants of a certain size. At this time, the solution was added to the concentration of 250 ppm of the electrodeposition (Tween-20) component (500ppm for rice). The plants sprayed with the medicament were left at room temperature for 24 hours to diffuse 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, if the control value is more than 90% at the first concentration (250ppm) of the chemical solution, the concentration is lowered from the first test concentration (250ppm) of the chemical solution at this time to control each fungus at the second test concentration (50ppm). Was measured.

The control effect was tested for all of the compounds obtained in Examples 1 to 44, and the control effect was expressed as Control Value (CV) for each plant pathogen of each compound used, and the control value was obtained according to the following formula. .

[Equation 1]

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 "Phytopathic area rate survey criteria table" (Kwang-Yeon Cho, 1989, Korea Research Institute for Chemical Development).

Test Example 1 Test for Rice Blast (RCB)

Pyricularia oryzae Cavara, a pathogen, KA301 strain was inoculated in rice bran agar medium (rice bran 20g, textloss 10g, agar 15g, distilled water 1L) and incubated for one week in a 26 ℃ incubator. The pathogen-grown medium was scraped off the surface of the medium with a rubber gallbladder to remove airborne microorganisms, and cultured for 48 hours on a fluorescent lamp-on shelf (25 ° C.-28 ° C.) to form spores. The conidia formed with germ inoculation were made to produce a certain concentration of spore suspension (spore concentration 1 × 106 spores / ml) using sterilized distilled water, and then enough to flow down to Nakdong rice (3-4 leaf stage) susceptible to rice blasting. 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 ± 21 ° C. to induce the disease for 5 days, and then investigated 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.

Test Example 2: Test for Rice Sheath Blight (RSB)

Inoculate a proper amount of bran into a 1ℓ bottle and sterilize it, and inoculate the Agar Disc of Rhizoctonia solani AG-1, a pathogen grown on a PDA plate for 3 days, and then in a 27 ± 1 ° C thermostat. 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 investigated according to the standard area ratio comparison table, which was prepared based on the ratio of lesion area to leaf area invented in the leaves of rice seedlings in the 2-3 leaf stage.

Test Example 3: Test for Cucumber Gray Mold Rot (CGM)

Botrytis conerea, isolated from cucumber gray mold disease, was inoculated in potato agar medium (PDA) and incubated for 15 days under light dark conditions 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 of diseased area formed on the leaves of cucumbers, based on the comparison of the standard area of disease-free control (control value; CV) with no drug treatment.

Test Example 4: Test for tomato late blight (TLB)

Spores (Phytophthora infestans) were placed on juice agar (V-8 juice 200ml, CaCO ³ 4.5g, agar 15g, distilled water 800ml) medium and incubated for 14 days after 16 hours light treatment and 8 hours 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.

Test Example 5: Test for Wheat Leaf Rust (WLR)

Puccinia recondita, a pathogen, was used for passage in plants in a laboratory. For subculture and pharmacological investigation of the monarch, 15 g of wheat seeds (silver onions) were sown in disposable pots (6.5 cm in diameter), and spores were inoculated by cultivating one leafy 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.

Test Example 6: Test for Barley Powdery Mildew (BPM)

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.

Compounds showing a control value of 90% or more at the 250 ppm primary test concentration in Test Example 1-6 were assayed for bactericidal activity at the 50 ppm secondary test concentration, and the results are shown in Table 3 below.

As can be seen from the results of Table 3, the novel propenoic ester and amide compounds (I) having a fluorovinyl group according to the present invention have a wider control range for the target strain and superior pharmacological efficacy and desirable effects than the existing compounds. It shows 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.

The results of assaying bactericidal activity against rice fever, wheat rust, and barley flour at lower concentrations of 10 ppm for compounds with more than 90% control at 50 ppm, the second test concentration, are shown in Tables 4, 5 and 6. Respectively.

TABLE 3a

Test result of bactericidal activity (treatment concentration: 50ppm)

TABLE 3b

TABLE 4

Bactericidal Activity against Rice Fever (Treatment Concentration: 10ppm)

TABLE 5

Bactericidal Activity against Wheat Rust Disease (Concentration: 10ppm)

TABLE 6

Bactericidal Activity against Wheat Flour Disease (Concentration: 10ppm)

As can be seen from the results of the drug efficacy test, novel propenoic ester and amide derivatives having a fluorovinyl group according to the present invention show excellent bactericidal activity even at low concentrations and have a wide antibacterial range.

Claims (4)

Novel propenoic ester or amide derivatives having a fluorovinyl group of the general formula (I) below; [Formula 1]

Wherein X represents CH or N, Y represents O or S, Z represents O or NH, and R represents hydrogen, alkyl having 1 to 4 carbon atoms or phenyl or naphthyl substituted by alkoxy, phenoxy, halogen Group. The propenoic ester or amide derivative according to claim 1, wherein in formula (I), X is A or N, Z is oxygen, and R is phenyl substituted with Cl or F. The bromide of the following general formula (IV) is reacted with 3-hydroxyphenol in the presence of a base to obtain a phenolic compound of the general formula (II), which is present in the presence of a vinyl fluoride compound of the general formula (III) and a base A process for the preparation of a compound of formula (I) according to claim 1 comprising reaction [Formula 2]

[Formula 3]

[Formula 4]

Wherein X, Y, Z and R are each as defined above. A fungicide composition comprising an effective amount of a propenoic ester or amide derivative having a fluorovinyl group of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.