JPH04217673A - 1,2,4-oxadiazole derivative and preparation thereof - Google Patents

Abstract

PURPOSE: To provide a new 1,2,4-oxadiazole derivative having excellent insecticidal and acaricidal effects and having a wide spectrum.

CONSTITUTION: This compound is represented by formula I (R¹ is fluoromethyl, alkoxymethyl, alkylaminocarbonylthiomethyl or the like, and at least one or R¹ and R² should be fluoromethyl), e.g. 3-(4'-bromophenyl)methyl-5- fluoromethyl-1,2,4-oxadiazole. The compound, for example that of formula III is formed by cyclizing O-acylamidoxime compound of formula II (R² is halogen, alkoxy or the like) in an organic solvent such as acetone, alcohol, dioxane or the like, preferably in the presence of a catalyst such as trifluoroboron etherate or the like.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to novel 1,2,4-oxadiazole derivatives in which either the 3 or 5 position is substituted with fluoromethyl and are useful as insecticides, acaricides and ovicides. and its manufacturing method.

0002

[Prior Art and Problems to be Solved by the Invention] A variety of 1,2,4-oxadiazole compounds have been developed since 1960, and research on their physiological activities has revealed that many compounds have been used as anesthetics, analgesics, and anti-inflammatory drugs. It is used as a medicine such as a drug.

[0003] Recently, organic compounds containing heterocycles such as thiazole, thiadiazole, isoxazole, and pyrazole have been developed as fungicides, insecticides, herbicides, and the like. In particular, compounds that have a 1,2,4-oxadiazole structure substituted on the side chain of pyrethroid, organophosphorus, and carbamate compounds, which are known as the main structures of insecticides, and have insecticidal effects with a new mode of action. 1, 2,
4-Oxadiazole compounds are disclosed in West German Patent Application Nos. 2,310,287 and 2,312,45.
No. 3, No. 2,312,500, No. 2,343
, No. 548, No. 2,406,786, No. 2,
No. 451,588, No. 2,430,758, No. 2,620,615, No. 3,010,319
No. 3,135,236, U.S. Patent No. 3,85
No. 6,897, No. 3,976,657, No. 4
, No. 134,985, No. 4,213,973,
It is disclosed in specifications such as French Patent No. 2,154,279 and European Patent No. 0,325,336.

[0004] However, it is necessary for insecticides to have a strong insecticidal action and a wide insecticidal spectrum, and since conventional insecticides are not necessarily satisfactory in these aspects, new A new insecticide is desired.

[0005]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors conducted extensive research and examination, and found that
, 2,4-oxadiazole derivatives have excellent insecticidal and acaricidal effects and have a wide spectrum, leading to the completion of the present invention.

In particular, the compound of the present invention is effective against aphids and mites, and can control them at the same time.
It was also found that it has an ovicidal effect on ticks, killing not only adults but also eggs. In addition to these, it also has the advantage of having an insecticidal effect on planthoppers and diamondback moths.

That is, the present invention has the general formula (I):

0
008]

[Chemical formula 12]

(wherein R1 is fluoromethyl; alkoxymethyl; alkylaminocarbonylthiomethyl;
Alkoxyphosphonylthiomethyl; phenylcarbonyloxymethyl substituted or unsubstituted with halogen or alkyl; phenyl substituted or unsubstituted with halogen or nitro; phenylmethyl substituted or unsubstituted with halogen, nitro or alkoxy phenoxymethyl substituted or unsubstituted with halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy; thiophenoxymethyl substituted or unsubstituted with halogen or alkyl; phenylsulfonylmethyl substituted with halogen; pyridinethio methyl; pyrimidinethiomethyl; or pyrazolethiomethyl and R2 is fluoromethyl; phenyl substituted or unsubstituted with halogen, alkoxy or alkyl; phenylmethyl substituted or unsubstituted with halogen, alkoxy or nitro; halogen, alkyl, trifluoromethyl, alkoxy or nitro substituted or unsubstituted phenoxymethyl or thiophenoxymethyl; or phenylsulfonylmethyl substituted with halogen, where R
The present invention relates to a fluoromethyl-substituted 1,2,4-oxadiazole derivative represented by (1 and R2 must be fluoromethyl and cannot be both fluoromethyl at the same time) and a method for producing the same.

0010

[Example] In the compound of the present invention represented by general formula (I), "alkyl" means alkyl having 1 to 4 carbon atoms, and "alkoxy" means alkyl having 1 to 3 carbon atoms. means.

Among the new compounds of general formula (I), particularly preferred are R1 in which R1 is fluoromethyl; phenylmethyl substituted or unsubstituted with halogen, nitro or alkoxy; halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy is substituted or unsubstituted phenoxymethyl; or halogen or alkyl is substituted or unsubstituted thiophenoxymethyl and R2 is fluoromethyl; halogen, alkoxy or nitro is substituted or unsubstituted phenylmethyl; or halogen, alkyl, trifluoromethyl, alkoxy or nitro is substituted or unsubstituted phenoxymethyl or thiophenoxymethyl, and one of R1 and R2 is necessarily fluoromethyl; It cannot be methyl.

Among the compounds of general formula (I), the most preferred are phenylmethyl in which one of R1 and R2 is fluoromethyl and the other is substituted with bromine or chlorine; bromine, chlorine, trifluoromethyl or phenoxymethyl substituted with methoxy; or thiophenoxymethyl substituted with bromine or chlorine.

Among the compounds of the present invention, 1,2,4-oxadiene substituted with 5-fluoromethyl, 5-fluoromethyl and 3-phenylmethyl, or 5-fluoromethyl and 3-phenoxymethyl are used. Azoles are particularly preferred for the purposes of the present invention, among which 3-
(4′-bromophenyl)methyl-5-fluoromethyl-1,2,4-oxadiazole, 3-(4
'-chlorophenoxy)methyl-5-fluoromethyl-1,2,4-oxadiazole and 3-(2
'-methoxyphenoxy)methyl-5-fluoromethyl-1,2,4-oxadiazole and the like are most preferred for purposes of this invention.

The compound of general formula (I) of the present invention can be produced by the following method.

Method for producing 3-fluoromethyl-1,2,4-oxadiazole derivative Method A or B shown below
is the general formula (Ia):

[0016]

[Chemical formula 13]

(wherein R2' is phenyl substituted or unsubstituted with halogen, alkoxy or alkyl; phenylmethyl substituted or unsubstituted with halogen, alkoxy or nitro; halogen, alkyl, trifluoromethyl, alkoxy or nitro-substituted or unsubstituted phenoxymethyl or thiophenoxymethyl; or halogen-substituted phenylsulfonylmethyl). available for use.

[0018] Method A

[0019]

[Chemical formula 14]

(In the formula, R2' is the same as above) Method B Stage 1:

[0021]

[Chemical formula 15]

Step 2: (wherein R2' is the same as above, M represents sodium, potassium, cesium or tetrabutylammonium)

[0023]

[Chemical formula 16]

(In the formula, R2' and M are the same as above)
In Method A, the O-acylamidoxime compound of general formula (II) is commercially available or can be synthesized using methods well known in the art. In method A, in an organic solvent, preferably in the presence of a catalyst such as trifluoroboron etherate,
heating to 0 °C, more preferably at the boiling point temperature of the solvent,
By carrying out the ring-closing reaction for 4 to 12 hours, the general formula (I
The 1,2,4-oxadiazole derivative of a) is obtained.

[0025] Examples of the organic solvent used here include acetone, alcohol, dioxane and toluene.

Method A is relatively simple and has high yields.

On the other hand, Method B is a preferable production method in that the target compound can be obtained more economically than Method A. In Step 1 of Method B, a 1,2,4-oxadiazole derivative of general formula (III) which is commercially available or can be easily synthesized using techniques known in the art is converted into a 1,2,4-oxadiazole derivative of general formula (IV). By reacting with alkali metal iodide or tetrabutylammonium iodide, a 1,2,4-oxadiazole derivative of general formula (V) can be produced. The organic solvent used in Method A can also be used in this reaction,
The reaction is preferably carried out at 55°C to 110°C, more preferably at the boiling temperature of the solvent for about 8 to 12 hours.

In step 2 of process B, the compound of general formula (V) obtained in step 1 and an alkali metal fluoride or tetrabutylammonium fluoride are combined in the presence of an organic solvent such as, for example, acetonitrile, preferably at 18 crowns. In the presence of ether catalyst, about 20 to 48
After a period of reaction, a compound of general formula (Ia) is obtained.

Depending on the substituent (R2'), slight changes may be made to Method A or Method B. For example, when the product of general formula (Ia) has a phenylsulfonylmethyl substituent at R2', an oxidation reaction as described in Example 46 provides a thiophenoxymethyl derivative.

Similar to the method for producing 5-fluoromethyl-1,2,4-oxadiazole derivatives, the general formula (I
b):

[0031]

[Chemical formula 17]

(wherein R1' is halogen or nitro-substituted or unsubstituted phenyl; halogen,
phenylmethyl substituted or unsubstituted with nitro or alkoxy; or phenoxymethyl substituted or unsubstituted with halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy)
Or general formula (Ic):

[0033]

[Chemical formula 18]

(wherein, R1″ is RCH2,
Alkoxymethyl; alkylaminocarbonylthiomethyl; alkoxyphosphonylthiomethyl; phenylcarbonyloxymethyl substituted or unsubstituted with halogen or alkyl; substituted or unsubstituted with halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy phenoxymethyl; thiophenoxymethyl substituted or unsubstituted with halogen or alkyl; pyridinethiomethyl; pyrimidinethiomethyl; pyrazolethiomethyl; or phenylsulfonylmethyl substituted with halogen);
Fluoromethyl-1,2,4-oxadiazole derivatives can be produced.

[0035] Method C

[0036]

[Chemical formula 19]

(wherein R1' and M are the same as above)
Method D Step 1:

[0038]

[C20]

(wherein M is the same as above) Step 2:

[0040]

[C21]

(wherein R is alkoxy; alkylaminocarbonylthio; alkoxyphosphonylthio; halogen or alkyl substituted or unsubstituted phenylcarbonyloxy; halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy phenoxy substituted or unsubstituted; thiophenoxy substituted or unsubstituted with halogen or alkyl;
represents pyridinethio; pyrimidinethio; pyrazolethio; or phenylsulfonyl substituted with halogen;
M and R1'' are the same as above) Method C is a general formula (Ib
This method is particularly useful for compounds shown in ). In the case of compounds having other R1 substituents that are not included in R1', method C is used because the fluorine ions of the compound represented by general formula (VI) attack the R1 substituents.
It is undesirable to manufacture by

In method C, 1 of general formula (VII)
, 2,4-oxadiazole derivatives are commercially available or can be easily synthesized by methods well known in the art, and these derivatives and general formula (VI)
of alkali metal fluoride or tetrabutylammonium fluoride are reacted under the same reaction conditions as in Step 2 of Method B to produce a compound of general formula (Ib).

On the other hand, method D is useful for producing compounds of general formula (Ic).

In Step 1 of Method D, a 1,2,4-oxadiazole derivative of general formula (VIII) and a 1,2,4-oxadiazole derivative of general formula (V
5- of general formula (IX) by reacting the alkali metal fluoride or tetrabutylammonium fluoride of I) under the same reaction conditions as in step 2 of method B.
A fluoromethyl-1,2,4-oxadiazole derivative is obtained.

Furthermore, in step 2 of method D, the 1,2,4-oxadiazole derivative of general formula (IX) obtained in step 1 and the nucleophile of general formula (X) are mixed with tetrahydrofuran (THF), Dimethyl formaldehyde (
The general formula (I
The 5-fluoromethyl-1,2,4-oxadiazole derivative c) is obtained. The reaction time is preferably about 5 to
It is 20 hours.

Similar to methods A or B, slight modifications may be made to methods C or D. For example, as in Example 109 described below, an oxadiazole substituted with phenylsulfonylmethyl can be synthesized from the corresponding thiophenoxymethyl compound by an oxidation reaction.

The present invention will be explained in detail below with reference to specific examples, but the present invention is not limited to these examples. Examples 1-19, compounds of the invention were prepared by Method A; Examples 20-45, Method B; Examples 47-6
1 indicates production by method C; Examples 62-108 indicate production by method D, respectively. Examples 46 and 109
As mentioned above, this explains the possibility of changing the manufacturing method.

The compounds produced in each example are listed in Table 1 using the example number as the compound number.

Example 1 This example shows that one of the preferred compounds, 3-fluoromethyl-5-(4'-chloro)phenyl-1,2,4-oxadiazole, was used in Method A.
This shows that it can be manufactured by

[0050]

[C22]

(1) Synthesis of fluoroacetamidoxime The fluoroacetamidoxime compound used in the above (formula A') can be easily synthesized as follows.

Hydroxylamine hydrochloride 6 in 25 ml of water
．． 95g (0.1 mol) and 10.6g of sodium carbonate
(0.1 mol) and then added 5.9 g (0.1 mol) of fluoroacetonitrile while keeping the temperature of the reaction solution below 0°C.
1 mol) was gradually added dropwise. After stirring for 30 minutes, the reaction solution was extracted twice with 50 ml of ether, the resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated at room temperature, i.e., 18-20°C, to give white crystals 8.
．． 1 g was obtained (yield: 89%).

The 1H-NMR analysis values of the obtained title compound are shown below.

1H-NHR (acetone-d6, TMS) (δ,
ppm): 8.23 (b, 1H), 5.32 (d, 2H
), 4.80(d,2H) (2) Synthesis of 3-fluoromethyl-5-(4'-chloro)phenyl-1,2,4-oxadiazole (1) Fluoroacetamidoxime 1. After dissolving 38 g (0.015 mol) and 2.63 g (0.015 mol) of 4-chlorobenzoyl chloride in 150 ml of dioxane, 0.14 g (0.001 mol) of trifluoroboron etherate was added, and 6
The mixture was heated to reflux for an hour. The organic layer obtained by filtering the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: ethyl acetate; n-hexane = 1:4) to obtain 2.4 g of a white solid with a melting point of 63°C. (Yield: 75
%).

Elemental analysis values of the obtained target compound and
The 1H-NMR analysis values are shown below.

Examples 2-19 Eight different compounds were prepared from substituted benzoyl chloride or substituted phenylacetyl chloride using a method similar to Example 1. All compounds were purified using column chromatography, and the molecular structure, physical properties, elemental analysis values, and 1H-NMR analysis values were
It was as shown in the table.

Example 20 This example shows 3-3, one of the preferred compounds of the present invention.
This shows that fluoromethyl-5-(2'-4'-dichlorophenoxy)methyl-1,2,4-oxadiazole can be produced by Method B.

[0058]

[C23]

[0059]

[C24]

(1) 3-iodomethyl-5- (2',4'-
3-chloromethyl-5-(2',4'-dichlorophenoxy)methyl-1,2, used as a starting material in the synthesis of dichlorophenoxy)methyl-1,2,4-oxadiazole (formula B1') 4-Oxadiazole was synthesized as follows. Dissolve 6.95 g (0.1 mol) of hydroxylamine hydrochloride and 10.6 g (0.1 mol) of sodium carbonate in 25 ml of water, keep the temperature of the reaction solution below 0°C, and dissolve 7.55 g of chloroacetonitrile. (0.1 mol) was slowly added dropwise. After stirring for 30 minutes, the reaction solution was extracted twice with 50 ml of ether, the resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated at room temperature to obtain 7.60 g of chloroacetamidoxime in the form of colorless needle-like crystals. This was washed and dried using hexane (yield: 70%).

The 1H-NMR analysis values of the obtained compound are shown below.

1H-NMR (CDCl3, TMS)
(δ, ppm): 8.40 (b, 1H), 5.31 (
b, 2H), 4.00 (s, 2H) 2.17 g (0.02 mol) of chloroacetamidoxime prepared as above and 4.7 g of 2,4-dichlorophenoxyacetyl chloride
9 g (0.02 mol) in 50 ml of dry toluene,
2.02 g (0.02 mol) of triethylamine was mixed and reacted at room temperature for 30 minutes with stirring. The organic layer obtained by washing the reaction product with 100 ml of water was dried over anhydrous sodium sulfate and concentrated under reduced pressure of 10 mmHg. The residue was purified using column chromatography (elution solvent, benzene:ether = 4:1) to a melting point of 92°C.
5.92 g of white solid O-(2,4-dichlorophenoxy)acetylchloroacetamidoxime was obtained (
Yield: 95%).

The 1H-NMR analysis values of the obtained compound are shown below.

1H-NMR (CDCl3, TMS) (δ, pp
m): 7.30-6.80 (m, 3H), 6.20 (b
, 2H), 4.90 (s, 2H), 4.12 (s, 2H)
) 3.12 g of O-(2,4-dichlorophenoxy)acetylchloroacetamidoxime prepared as above.
(0.01 mol) was dissolved in 150 ml of dioxane, and 0.14 g (0.0 mol) of trifluoroboron etherate was dissolved in 150 ml of dioxane.
01 mol) was added thereto, and the mixture was heated under reflux for 6 hours. The reaction solution was filtered, the organic layer was concentrated under reduced pressure conditions of 10 mmHg, and the residue was purified using column chromatography (elution solvent, benzene:ether = 9:1) to obtain 3 as a white solid with a melting point of 66°C. -chloromethyl-5- (2',4'-
1.91 g of dichlorophenoxy)methyl-1,2,4-oxadiazole was obtained (yield: 65%).

The 1H-NMR analysis values of the obtained compound are shown below.

1H-NMR (CDCl3, TMS) (δ, pp
m): 7.30-6.80 (m, 3H), 5.25 (s
, 2H), 4.55 (s, 2H) 3-chloromethyl-5-(2',4'-dichlorophenoxy)methyl-1,2,4-oxadiazole 1 prepared as above
．． 76g (0.006 mol) and potassium iodide 1.0
g (0.006 mol) in 50 ml of dry acetonitrile
1, 0.1 g of 18-crown ether as a phase transfer catalyst was added, and the mixture was heated under reflux for 20 hours. The reaction solution was concentrated and extracted with 50 ml of ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was subjected to column chromatography (eluent: ethyl acetate:hexane = 1:4). 1.96 g of product was obtained (yield: 82%).

The 1H-NMR analysis values of the obtained title compound are shown below.

1H-NMR (CDCl3, TMS) (δ, pp
m): 7.30-6.80 (m, 3H), 5.25 (s
, 2H), 4.30(s,2H)(2) Synthesis of 3-fluoromethyl-5-(2',4'-dichlorophenoxy)methyl-1,2,4-oxadiazole Produced as described above. 3-iodomethyl-5- (2',
4'-dichlorophenoxy)methyl-1,2,4-
1.0 g (0.0026 mol) of oxadiazole and 1.22 g (0.008 mol) of cesium fluoride dissolved in 30 ml of dry acetonitrile were added to 1.0 g (0.0026 mol) of the phase transfer catalyst.
0.05 g of 8-crown ether was added, and the mixture was heated under reflux for 16 hours. Concentrate the reaction solution and add 30ml of ethyl acetate.
The extract was extracted with 1 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to column chromatography (
Purification was performed using an eluent (ethyl acetate:hexane=1:4) to obtain 0.46 g of product (yield: 64%).

Elemental analysis values of the obtained target compound and
The 1H-NMR analysis values are shown below.

1H-NMR (CDCl3, TMS) (δ,
ppm); 7.40-7.20 (m, 3H), 5.50
(d,2H), 5.40(s,2H) Examples 21-45 Twenty-five different compounds listed in Table 1 were prepared from substituted phenoxyacetyl chloride or substituted thiophenoxyacetyl chloride. Manufactured using the method of Example 20. All compounds were purified by column chromatography, and their molecular structures, physical properties, elemental analysis values, and 1H-NM
The analytical values of R are shown in Table 1.

Example 46 This example shows 3-3, one of the preferred compounds of the present invention.
This shows that fluoromethyl-5-(4'-chloro)phenylsulfonylmethyl-1,2,4-oxadiazole is produced from the corresponding thiophenoxymethyloxadiazole compound by an oxidation reaction.

[0072]

[C25]

0.27 g (0.27 g) of 3-fluoromethyl-5-(4'-chloro)thiophenoxymethyl-1,2,4-oxadiazole obtained in Example 44.
001 mol) and m-chloroperbenzoic acid 0.43 g (0
．． 0025 mol) in 10 ml of dichloromethane,
The mixture was stirred at room temperature for an hour. The reaction solution was washed with saturated sodium bicarbonate and 10% sodium sulfite, extracted with dichloromethane, dried over anhydrous sodium carbonate, and the solvent was distilled off. The obtained residue was subjected to column chromatography (elution solvent, ethyl acetate:hexane = 1:
1) to obtain 0.28 g of product (yield: 90
%).

Elemental analysis values of the obtained target compound and
The 1H-NMR analysis values are shown below.

1H-NMR (CDCl3, TMS) (δ,
ppm); 7.90-7.40 (m, 4H), 5.40
(d,2H), 4,70(s,2H) Example 47 This example shows 3-
(2′-chlorophenyl)-5-fluoromethyl-
1,2,4-oxadiazole is produced by method C.

[0076]

[C26]

(1) The starting material used in the synthesis of 3-(2'chlorophenyl)-5-chloromethyl-1,2,4-oxadiazole (formula C') can be synthesized as follows. can. Hydroxylamine hydrochloride 8.3 g
(0.12 mol) and 10.1 g (0.1 mol) of sodium carbonate
Dissolve 2 mol) in 50 ml of water and add 100 ml of ethyl alcohol.
13.7 g of 2-chlorobenzonitrile in ml (0.
After adding 1 mol), the mixture was heated under reflux at 78°C for 6 hours. The reaction solution was concentrated under reduced pressure to 10 mmHg, extracted with 100 ml of ethyl acetate, dried over anhydrous magnesium sulfate to remove the solvent, and washed with benzene to obtain product 13.
6 g was obtained (yield: 80%).

To 100 ml of 1,4-dioxane was added 12.5 g (0.073 mol) of 2-chlorophenylacetamidoxime prepared as described above, and while maintaining the temperature of the reaction solution at 0°C, 8.25 g (0.0 mol) of chloroacetyl chloride was added to 100 ml of 1,4-dioxane.
．． 073 mol) was gradually added dropwise. After completely adding chloroacetyl chloride, the temperature of the reaction solution was raised to 70°C, 0.14 g (0.001 mol) of boron fluoride etherate was added, and the mixture was heated under reflux at 100°C for 5 hours. After distilling off the solvent under reduced pressure to 10 mmHg, ethyl acetate 1
00 ml, dried over anhydrous sodium sulfate, and further distilled off the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 3-(2'-chlorophenyl)-
11.7 g of 5-fluoromethyl-1,2,4-oxadiazole product was obtained (yield: 70%).

(2) Synthesis of 3-(2'-chlorophenyl)-5-fluoromethyl-1,2,4-oxadiazole (1) 3-(2'-chlorophenyl)-5-chloromethyl- 10.6 g (0.046 mol) of 1,2,4-oxadiazole and 20.0 g of cesium fluoride (
0.138 mol) was heated to reflux at 82° C. for 16 hours. The organic layer obtained by washing the reaction solution with water was dried over anhydrous magnesium sulfate, and the solvent was concentrated and removed under reduced pressure conditions of 10 mmHg. = 1:4) to obtain 4.89 g of product (yield:
50%).

Elemental analysis values of the obtained compound and 1H
-NMR analysis values are shown below.

1H-NMR (CDCl3, TMS) (δ,
ppm); 7.50-6.90 (m, 4H), 5.60
(d,2H) Examples 48-61 Fourteen different compounds were prepared from substituted phenyl or substituted phenylmethylnitrile using the method of Example 47. All compounds are purified by column chromatography, and their molecular structure, physical properties, elemental analysis values, and
The 1H-NMR analysis values are shown in Table 1.

Example 62 This example shows 3, which is one of the preferred compounds of the present invention.
-methoxymethyl-5- fluoromethyl-1,2,4
- Demonstrates that oxadiazoles are prepared by method D.

[0083]

[C27]

[0084]

[C28]

(1) 3-chloromethyl-5-fluoromethyl-1
, 2,4-oxadiazole synthesis above (formula D1')
The starting materials used in can be synthesized as follows.

6.95 g (0.1 mol) of hydroxylamine hydrochloride and 10.6 mol of sodium carbonate in 25 ml of water
g (0.1 mol) of the reaction solution while keeping the temperature below 0°C.
was gradually added dropwise. After stirring for 30 minutes, dilute the reaction solution with ether 5
The organic layer obtained by extraction twice with 0ml was dried over anhydrous sodium sulfate, and the solvent was evaporated at room temperature, i.e., 18-20°C, to obtain chloroacetamide oxime 7 as colorless needle-like crystals.
．． 60 g was obtained (yield: 70%).

The 1H-NMR analysis values of the obtained compound are shown below.

1H-NMR (CDCl3, TMS)
(δ, ppm): 8.40 (b, 1H), 5.31 (
b, 2H), 4.00 (s, 2H) methylene chloride 100
7.1 g (0.065 mol) of the chloroacetamidoxime produced in (1) and 9.1 ml (0.065 mol) of triethylamine were added to the reaction mixture while keeping the temperature below 5°C. 5.2 ml (0.065 mol) of chloroacetyl chloride was slowly added dropwise. After stirring for 1 hour, the reaction solution was washed with 100 ml of water, and the resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (elution solvent, ethyl acetate:hexane = 1:1) to obtain O-chloroacetylchloroacetamide oxime 10 as a white solid.
．． 2 g was obtained (yield: 85%).

In 100 ml of dry toluene, 10.1 g (0.054 mol) of O-chloroacetylchloroacetamidoxime prepared as described above and 0.28 g (0.002 mol) of boron fluoride etherate were added to 110 ml of dry toluene.
While heating under reflux at ℃ for 4 hours, 1 ml of water produced was removed. The reaction solution was concentrated under reduced pressure at 10 mmHg, and the resulting residue was distilled under reduced pressure to give a boiling point of 86 to 88°C at 3 mmHg.
7.2 g of liquid was obtained (yield: 80%).

3,5-dichloromethyl-1,2 prepared as above in 100 ml of dry acetonitrile.
, 7.0 g (0.042 mol) of 4-oxadiazole was dissolved, and 19.3 g (0.13 mol) of cesium fluoride and 18-crown-6-ether (0.05 g) were added as a phase transfer catalyst. , and heated under reflux for 20 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure.The resulting residue was vacuum distilled to a boiling point of 64-66 at 2 mmHg.
4.55 g of liquid at ℃ was obtained (yield: 72%).

(2) 3-methoxymethyl-5-fluoromethyl-
Synthesis of 1,2,4-oxadiazole Acetonitrile 5
0 ml of 3-chloromethyl- prepared as above.
5-fluoromethyl-1,2,4-oxadiazole 0.3 g (0.002 mol), methanol 0.6
4g (0.002 mol) and potassium carbonate 0.276
g (0.002 mol) was added and the mixture was heated to reflux at 82° C. for 6 hours. After concentrating the reaction solution, add 50ml of ethyl acetate.
After drying the organic layer with anhydrous sodium sulfate and removing the solvent, the obtained residue was purified by column chromatography (elution solvent: ethyl acetate:hexane = 1:4) to obtain 0.21 g of an oily substance. (yield: 72%).

Elemental analysis values of the obtained compound and 1H
-NMR analysis values are shown below.

1H-NMR (CDCl3, TMS) (δ,
ppm); 5.50 (d, 2H), 5.30 (s, 2H
), 2.30 (s, 3H) Examples 63 to 10846 different compounds from substituted thio anions or substituted phenyl, benzyl, pyridic acids to Example 62
It was manufactured using the method of All compounds were purified by column chromatography, and the molecular structures, physical properties, elemental analysis values, and 1H-NMR analysis values are as shown in Table 1.

Example 109 This example shows 3, one of the preferred compounds of the present invention.
-(4′-chloro)phenylsulfonylmethyl-5
- Fluoromethyl-1,2,4-oxadiazole can be synthesized by oxidizing the final product synthesized in Example 101.

[0095]

[C29]

3-(4) produced in Example 101
'-Chloro)thiophenoxymethyl-5-fluoromethyl-1,2,4-oxadiazole 1.5 g (0
．． 0058 mol) and 2.07 g of m-chloroperbenzoic acid
was added to 50 ml of dichloromethane and stirred at room temperature for 5 hours. The reaction solution was washed with saturated sodium hydrocarbon and 10% sodium sulfite, extracted with dichloromethane, dried over anhydrous sodium carbonate, and the solvent was distilled off. The obtained residue was purified by column chromatography (elution solvent: ethyl acetate:hexane=1:1) to obtain 1.53 g of product (yield: 91%).

Elemental analysis values of the obtained compound and 1H
-NMR analysis values are shown below.

1H-NMR (CDCl3, TMS) (δ, p
pm) ; 8.00 to 7.60 (q, 4H), 5.
70 (d, 2H), 4.90 (s, 2H)

0099

[Table 1]

[0100]

[Table 2]

[0101]

[Table 3]

[0102]

[Table 4]

[0103]

[Table 5]

[0104]

[Table 6]

[0105]

[Table 7]

[0106]

[Table 8]

[0107]

[Table 9]

[0108]

[Table 10]

[0109]

[Table 11]

[0110]

[Table 12]

[0111]

[Table 13]

[0112]

[Table 14]

Test Example (Insecticidal Activity Test) The insecticidal activity of the compounds of the present invention produced in Examples was biologically assayed as follows.

(1) Brown Planthopper (BPH) Each test compound was dissolved in 5 ml of acetone (100%) to the required concentration in Triton X-100 (purchased from Yakuri Kagaku Kogyo Co., Ltd., Japan). Ta.

[0115] The roots of six 4-5 cm Higashitsu rice seedlings were wrapped with absorbent cotton and placed in a test tube (φ3×
15cm). Twenty adult brown planthoppers were captured with fluke tubes 3 to 5 days after emergence, and were then released and inoculated into test tubes. 50 μl of a test compound solution of a predetermined concentration was sprayed using a microsprayer. After covering the inlet of the test tube, the test tube was stored in a thermostat at 25° C. and the mortality rate was examined after 48 hours. The results of the insecticidal test of the compound against the brown planthopper are shown in Table 3.

(2) Diamondback moth (DBM) Cabbage leaves in a uniformly developed state were cut into 5 cm diameter pieces, immersed in a test compound solution for 30 seconds, and then air-dried for 30 minutes. Place the treated leaves in a Petri dish (φ5 x 1 cm) lined with filter paper.
) and inoculated with 10 third instar larvae. The test container was covered and stored in a thermostat at 25° C., and the mortality rate was investigated after 48 hours. The results of the insecticidal test of the compound against the diamondback moth are shown in Table 3.

(3) Green peach aphid (GPA) or cotton aphid (CA) Tobacco leaves with a diameter of 5.5 cm were immersed in the test compound solution for 30 seconds and then air-dried for 30 minutes. Place the treated leaves in a plastic Petri dish (φ5.5 x 2c) lined with filter paper.
m) and inoculated with 20 wingless female worms. The test container was covered and stored in a thermostat at 25° C., and the mortality rate was investigated after 48 hours. The results of the insecticidal test of the compounds against green peach aphid are shown in Table 3.

(4) Two-spotted spider mite (TSSM) Spread absorbent cotton in a plastic Petri dish (φ5.5 x 2 cm), fill it with a certain amount of water, place a leaf with a diameter of 2.5 cm on top of it, and place 30 adult spider mites on it. Animals were inoculated using a fine brush. 0.53 ml of a test compound solution of a predetermined concentration was sprayed using a microsprayer. The mortality rate was investigated after 48 hours while being stored in a thermostat at 25°C.

[0119] In the ovicidal test, 10 adults were inoculated onto a 2.5 cm diameter kidney bean leaf piece, allowed to lay eggs for 24 hours, the adults were removed, the density was checked in advance, and the test compound solution was inoculated for 10 seconds. Soaked. After the treatment, the cells were stored in a constant temperature chamber at 25° C., and the hatching inhibition rate was investigated after 7 days. The results of the insecticidal test of the compound against two-spotted spider mites are shown in Table 3.
The results of the insecticidal test for the ovicidal test are shown in Table 4.

The mortality rate was measured using the following formula.

[0121]

[Math 1]

The abbreviations of the test insects used in the above insecticidal activity tests are shown in Table 2.

[0123]

[Table 15]

[0124]

[Table 16]

[0125]

[Table 17]

[0126]

[Table 18]

[0127]

[Table 19]

[0128]

[Table 20]

The insecticidal activity of the compounds of the invention prepared in Examples 30, 52 and 93 above is shown in Table 5 in comparison to compounds known in the art. L in Table 5
C50 values are determined from the percentage kill measured for various concentrations of the compound using the analytical method described above. As can be seen from Table 5, the compounds of the present invention have superior and broad-spectrum insecticidal properties compared to known compounds widely used in this field.
It showed acaricidal or ovicidal activity.

[0130]

[Table 21]

[0131]

Effects of the Invention The production method of the present invention produces a novel compound represented by the general formula (I) in which fluoromethyl is substituted at either the 3 or 5 position of 1,2,4-oxadiazole. Can be synthesized. These 1,2,4-oxadiazole derivatives are excellent not only in insecticidal and acaricidal effects but also in ovicidal effects against eggs of mites and the like, and are further characterized in that they have a wide spectrum. These derivatives are particularly effective against aphids and mites, and also have considerable insecticidal effects against other lepidopterans, planthoppers, and diamondback moths.

Claims (10)

[Claims] [Claim 1] General formula (I): [Formula 1] (wherein, R1 is fluoromethyl; alkoxymethyl;
Alkylaminocarbonylthiomethyl; alkoxyphosphonylthiomethyl; phenylcarbonyloxymethyl substituted or unsubstituted with halogen or alkyl; phenyl substituted or unsubstituted with halogen or nitro; substituted with halogen, nitro or alkoxy; or unsubstituted phenylmethyl; halogen;
phenoxymethyl substituted or unsubstituted with alkyl, trifluoromethyl, alkoxy or thioalkoxy; thiophenoxymethyl substituted or unsubstituted with halogen or alkyl; phenylsulfonylmethyl substituted with halogen; pyridinethiomethyl; pyrimidine thiomethyl; or pyrazolethiomethyl and R2 is fluoromethyl; phenyl substituted or unsubstituted with halogen, alkoxy or alkyl;
Phenylmethyl substituted or unsubstituted with halogen, alkoxy or nitro; phenoxymethyl or thiophenoxymethyl substituted or unsubstituted with halogen, alkyl, trifluoromethyl, alkoxy or nitro; phenylsulfonyl substituted with halogen A 1,2,4-oxadiazole derivative (representing methyl, provided that either R1 or R2 must be fluoromethyl and cannot be fluoromethyl at the same time). 2. In general formula (I), R1 is fluoromethyl; phenylmethyl substituted or unsubstituted with halogen, nitro or alkoxy; halogen,
Alkyl, trifluoromethyl, alkoxy or thioalkoxy substituted or unsubstituted phenoxymethyl; or halogen or alkyl substituted or unsubstituted thiophenoxymethyl and R2 is fluoromethyl; halogen, alkoxy or nitro is substituted phenylmethyl; or halogen, alkyl, trifluoromethyl, alkoxy or nitro substituted or unsubstituted phenoxymethyl or thiophenoxymethyl; one of R1 and R2 must be fluoromethyl; The 1,2,4-oxadiazole derivative according to claim 1, which is incapable of becoming a 1,2,4-oxadiazole derivative. 3. In general formula (I), R1 and R2 are each fluoromethyl; phenylmethyl substituted with bromine or chlorine; phenoxymethyl substituted with bromine, chlorine, trifluoromethyl or methoxy; or bromine or chlorine substituted; 2. The 1,2,4-oxadiazole derivative according to claim 1, which is a substituted thiophenoxymethyl, and one of R1 and R2 is necessarily fluoromethyl, but cannot be fluoromethyl at the same time. 4. The compound of general formula (I) is 3-(4
'-bromophenyl)methyl-5-fluoromethyl-1,2,4-oxadiazole
,2,4-oxadiazole derivative. 5. The compound of general formula (I) is 3-(4
The 1,2,4-oxadiazole derivative according to claim 1, which is methyl-5-fluoromethyl-1,2,4-oxadiazole ('-chlorophenoxy)methyl-5-fluoromethyl-1,2,4-oxadiazole. 6. The compound of general formula (I) is 3-(2
'-Methoxyphenoxy)methyl-5-fluoromethyl-1,2,4-oxadiazole Claim 1
A 1,2,4-oxadiazole derivative of. 7. General formula (II): [Image Omitted] (wherein R2' is phenyl substituted or unsubstituted with halogen, alkoxy or alkyl; Phenylmethyl; phenoxymethyl or thiophenoxymethyl substituted or unsubstituted with halogen, alkyl, trifluoromethyl, alkoxy or nitro; phenylsulfonylmethyl substituted with halogen); The ring-closing reaction is carried out in the presence of a solvent and a catalyst at a temperature of 55°C to 110°C for 4 to 12 hours, and is represented by general formula (Ia): [Chemical formula 3] (wherein R2' is the same as above). A method for producing a 3-fluoromethyl-1,2,4-oxadiazole compound. 8. General formula (III): [Formula 4] (wherein R2' is phenyl substituted with halogen, alkoxy or alkyl or unsubstituted; R2' is substituted with halogen, alkoxy or nitro or unsubstituted phenylmethyl; halogen, alkyl, trifluoromethyl, alkoxy, or nitro-substituted or unsubstituted phenoxymethyl or thiophenoxymethyl; or halogen-substituted phenylsulfonylmethyl); - Oxadiazole derivative with general formula (IV): MI
(IV) (wherein M represents sodium, potassium, cesium or tetrabutylammonium) is reacted with an alkali metal iodide or tetrabutylammonium iodide to form the general formula (V): [Formula 5] 1, 2, 4, where R2' is the same as above)
- After obtaining the oxadiazole derivative, this derivative is converted to the general formula (VI): MF (VI) (in the formula,
General formula (Ia) characterized by reacting with an alkali metal fluoride or tetrabutylammonium fluoride (M is the same as above): [Chemical formula 6] (wherein R2' is the same as above) A method for producing a 3-fluoromethyl-1,2,4-oxadiazole derivative. 9. General formula (VII): [Formula 7] (wherein, R1' is phenyl substituted with halogen or nitro or unsubstituted; phenylmethyl substituted with halogen, nitro or alkoxy or unsubstituted) ; halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy substituted or unsubstituted phenoxymethyl);
The 4-oxadiazole derivative has the general formula (VI): MF

General formula (Ib) characterized by reacting with an alkali metal fluoride or tetrabutylammonium fluoride represented by (VI) (wherein M represents sodium, potassium, cesium or tetrabutylammonium): 8] A method for producing a 5-fluoromethyl-1,2,4-oxadiazole derivative represented by the formula (wherein R1' is the same as above). 10. A 1,2,4-oxadiazole derivative represented by general formula (VIII): [Chemical formula 9] is converted into a 1,2,4-oxadiazole derivative represented by general formula (VI):
(VI) (wherein M is sodium,
5-fluoromethyl-1,2,4 represented by the general formula (IX): [Chemical formula 10] - After obtaining the oxadiazole derivative, this derivative is converted to the general formula (X
):RM
(X) (wherein R is alkoxy; alkylaminocarbonylthio; alkoxyphosphonylthio; phenylcarbonyloxy substituted or unsubstituted with halogen or alkyl; halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy phenoxy substituted or unsubstituted; thiophenoxy substituted or unsubstituted with halogen or alkyl;
represents pyridinethio; pyrimidinethio; pyrazolethio; or phenylsulfonyl substituted with halogen;
General formula (Ic) characterized by reacting with a nucleophile represented by the formula (M is the same as above): [Formula 11] (wherein, R1'' is RCH2, alkoxymethyl; alkylaminocarbonylthiomethyl; Alkoxyphosphonylthiomethyl; phenylcarbonyloxymethyl substituted or unsubstituted with halogen or alkyl; phenoxymethyl substituted or unsubstituted with halogen, alkyl, trifluoromethyl, alkoxy or thioalkoxy; substituted with halogen or alkyl or unsubstituted thiophenoxymethyl;
A method for producing a 5-fluoromethyl-1,2,4-oxadiazole derivative represented by pyridinethiomethyl; pyrimidinethiomethyl; pyrazolethiomethyl; or halogen-substituted phenylsulfonylmethyl.