JPS5822099B2 - N-benzyl-cycloalkylamine compound and method for producing the compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an N-benzyl-cycloalkylamine compound which is a raw material for producing a urea or thiourea compound having excellent bactericidal activity, and a method for producing the compound.

The N-benzyl-cycloalkylamine compound of the present invention has the general formula: (wherein, R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R2 is a carbon substituted with an alkyl group having 1 to 4 carbon atoms. A polymethylene group having 4 to 6 atoms or an unsubstituted polymethylene group having 4 to 6 carbon atoms, and X represents a halogen atom, a nitro group, a cyano group, or an alkyl group having 1 to 4 carbon atoms.

).

The compound of general formula (I) above can be produced, for example, by the following methods (A) and (B), and the present invention also relates to these production methods.

That is, (A) General formula: (In the formula, R1 and X are the same as above.

Hal represents a halogen atom.

) and the benzilno ride represented by General formula: (In the formula, R2 is the same as above.

A method for producing an N-benzyl-cycloalkylamine compound represented by the general formula α), which comprises reacting N-benzyl-cycloalkylamine represented by the formula α) with a cycloalkylamine represented by the formula α), if necessary in the presence of an acid binder.

(B) General formula: (In the formula, R1 and X are the same as above.

) N-benzylamine represented by General formula: (In the formula, R2 is the same as above.

) by reacting with a cyclic ketone represented by General formula: (In the formula, R1, R2 and X are the same as above.

A method for producing an N-benzyl-cycloalkylamine compound represented by the general formula (I), which comprises producing a Schiff base represented by the formula (I), and then reducing the Schiff base.

As a result of researching the physiological activity of novel urea or thiourea compounds, the present inventors have found that the N-benzyl-cycloalkylamine compound represented by the general formula (I) can be produced using the N-benzyl-cycloalkylamine compound as a production intermediate. We have discovered that urea or thiourea compounds have extremely excellent bactericidal activity.

The compound is the N-
It can be synthesized by reacting a benzyl-cycloalkylamine compound with various incyanates or inthiocyanates.

The novel urea or thiourea compounds obtained using the compounds of the present invention as production intermediates have excellent bactericidal and growth-inhibiting properties against plant pathogens, and are useful for eradicating plant diseases caused by a wide variety of fungi. It is particularly effective against plant diseases caused by basidiomycetes, such as rice sheath blight and seedling blight of various crops.

Urea or thiourea compounds obtained from the compounds of the present invention are pathogenic bacteria that parasitize the above-ground parts of plants, pathogenic bacteria that invade plants from the soil and cause tracheomycosis,
It can be used against seed-borne pathogens and soil-borne pathogens, has low toxicity to warm-blooded animals, and has good affinity for higher plants, i.e., has no phytotoxicity to cultivated plants at normal concentrations. Therefore, it can be used conveniently as an agricultural and horticultural agent against plant diseases caused by pathogenic bacteria.

In other words, archaeal bacteria [Archimycetes (Ar)] are used as fungicides.
chimycetes )), Phycomycetes (Phycomycetes), l, Ascomycetes [
Ascomycetes, l.
Basidiomycetes (Basidiomycetes)
It can be effectively used against various plant diseases caused by Fungi imperfecti, Fungi imperfecti, and other bacteria.

Pelicularia 5asakii (Pelicularia 5asakii) is a particularly important disease of rice.
) , ] , Pelicularia filamentosa is a fungus that causes seedling blight of various crops.
lamentosa), which has surprising activity against l.

In addition, there is a fungus called Corticium centrifugum (Corticium centrifugum) on various crops.
ugum) :l, blast fungus [Piricularia spp.
Pyricularia oryzae,
l, rice bacterial leaf blight [Xanthomonas oryzae (X
anthomonas oryzae), l, soft rot of Chinese cabbage mcErwinia aroideae], canker bacterium [Xanthomonas citri (Xanthomonas oryzae)],
homonascitri), l, the fungus that causes sesame flaking of rice [Cochliovora sumyabeanus (Cochliovora soumyabeanus)
bolus mlyabeanus), 1 banana leaf spot disease fungus [Mycospha
erella musicola )), gray mold fungus of strawberries and other crops [Botrytis cinerea (Botrytis cinerea), L, downy mildew fungus of grapes [Plasmopara
moparaviticola)), grapes, apples, and Glomerella singulata (Glomerella singulata)
Glomerella cingulata ), ]
, Sclerotinia sclerotiorum of soybeans [Sclerotinia sclerotiorum]
)), Cocollus stain fungus of cucurbits [CoCo11etotrichu agena
r member m)], black spot on cassava, disease fungus [Diaporthe citri, l, powdery mildew fungus on apples [Podosphaera leucotri force (Po)
dosphacra 1eucotricha), l
, powdery mildew fungus of cucumber [Sphaerotheca fuliginea (5phaerotheca fuliginea)]
) , ] , Bacteria that cause black spot disease 1 For example, the fungus that causes brown spot disease on apples [Alternaria mari (Alternaria
mali)), potato summer blight fungus [Alternaria 5olani], l, black spot fungus [Alternaria quictiana]
ariakikuchiana), 1st grade, bacteria that cause scab, such as apple scab [Pentulia spp.
Venturia 1naequal
It also exhibits remarkable activity against sclerotid fungi (Venturia pirina, 1, etc.).

As mentioned above, it has been confirmed that the compound of the present invention, which is a production intermediate for a novel urea or thiourea compound having excellent bactericidal properties, is extremely useful in industry.

The compound represented by the general formula (I) of the present invention is synthesized by the following general method.

[Method A]

(In the formula, R', R2, X and Hal are the same as above.

) In the above reaction formula, R1 is specifically a hydrogen atom, or methyl, ethyl, n-(or 1so-)propyl, n-(or 1so-1 or 5ec-1 or te
rt ) represents an alkyl group having 1 to 4 carbon atoms such as butyl.

R2 specifically has the same number of carbon atoms as listed for R1, from 1 to
represents a polymethylene group having 4 to 6 carbon atoms, such as tetramethylene, pentamethylene, hexamethylene, substituted with 4 alkyl groups or unsubstituted.

Specifically, X represents a halogen atom such as chloro, bromo, iodo, or fluoro, a nitro group, a cyano group, or an alkyl group having 1 to 4 carbon atoms as mentioned for R1.

Specifically, Hal represents a halogen atom such as chloro, bromine, iodine, or fluoro, preferably a chloro atom.

Further, in the method for producing the compound of general formula (I) shown in the above reaction formula example, general formula (6) as a raw material.

Specifically, the benzyl halides shown are 4-chlorobenzyl chloride, 4-bromobenzyl chloride, 4-methylbenzyl chloride, 4-nitrobenzyl chloride, 4-cyanobenzyl chloride, 4-chloro-α-methylbenzyl chloride, and their bromides.

Also, cyclo represented by the general formula (e) above, which is a raw material.

Specifically, alkylamines are cyclopentylamine, 3-methylcyclopentylamine, cyclohexylamine, 2-methylcyclohexylamine, 3-methylcyclohexylamine, 4-methylcyclohexylamine, Cycloheptylamine etc. can be mentioned.

Next, the above manufacturing method will be specifically explained using representative examples.

The method of the invention is preferably carried out using a solvent or diluent.

All inert solvents and diluents can be used for this purpose.

Such solvents or diluents include water; aliphatic cycloaliphatic and aromatic hydrocarbons (which may optionally be chlorinated) such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene. Chloride, chloroform, carbon tetrachloride, ethylene chloride and hydrychloroethylene, chlorobenzene; other ethers such as diethyl ether,
Methyl ethyl ether, di-1So-propyl ether, dibutyl ether, propylene oxide dioxane, tetrahydrofuran; ketones such as acetone, methyl ethyl ketone, methyl-1so-propyl ketone,
Nonal-1so-butylketone nitriles such as acetonitrile, propionitrile, acrylonitrile;
Alcohols such as methanol, ethanol, 1so
-7” lovanol, butanol, ethylene glycol;
Esters such as ethyl acetate, amyl acetate; acid amides such as dimethylformamide, dimethylacetamide; sulfones, sulfoxides such as dimethyl sulfoxide, sulfolane; and bases such as pyridine.

When carrying out the present invention, the reaction is carried out using twice the molar amount of amine, but the reaction can also be carried out in the presence of an equimolar amount of the acid binder relative to one molar amount of the amine.

Such acid binders include commonly used alkali metal hydroxides, carbonates, bicarbonates, alkoxides, etc., and tertiary amines such as triethylamine, diethylaniline, pyridine, etc. be able to.

The method of the invention can be carried out within a wide temperature range.

Generally carried out between -20°C and the boiling point of the mixture,
It is preferably carried out at a temperature of 0 to 100°C.

Further, although it is preferable to carry out the reaction under normal pressure, it is also possible to operate under increased pressure or reduced pressure.

[Method B]

(In the formula, R1, R2 and X are the same as above.

) In the method for producing the compound of general formula (I) shown in the above reaction formula example, the raw material N-
Specific examples of benzylamine include 4-chlorobenzylamine, 4-bromobenzylamine, 4-methylbenzylamine, 4-nitrobenzylamine, 4-cyanobenzylamine, and 4-chloro-α-methylbenzylamine. can.

In addition, the cyclic ketones represented by the general formula M that are raw materials are specifically cyclopentanone, 3-methylcyclopentanone, cyclohexanone, 2-methylcyclohexanone, 3-methylcyclohexanone, 4-methylcyclohexanone, and cyclohepta. Non etc. can be mentioned.

In addition, examples of reducing agents for the Schiff base represented by the general formula include sodium borohydride, lithium aluminum hydride, metallic sodium (alcohol), metallic magnesium (alcohol), catalytic reduction, and the like.

Next, the above manufacturing method will be specifically explained using representative examples.

In the above reaction, the Schiff base obtained as an intermediate can be isolated, but by subsequent reduction with sodium borohydride without isolation, the target N-4-chlorobenzyl-cyclopentylamine can be highly It can be obtained with high purity and high yield.

In order to carry out the above method, the same inert solvent or diluent as described above is preferably used, and the desired product can be obtained with high purity and high yield.

To prepare the compounds of the invention, it is possible to carry out within a wide temperature range.

Generally carried out between -20°C and the boiling point of the mixture,
It is preferably carried out at a temperature of 0 to 100°C.

Further, although it is preferable to carry out the reaction under normal pressure, it is also possible to operate under increased pressure or reduced pressure.

Next, a synthesis example will be shown and a method for producing the compound of the present invention will be specifically described.

Synthesis example 1 cyclopentylamine 170g, sodium hydroxide 40g
Dissolve the ingredients in 160ml of water and stir while cooling.
- Add chlorobenzyl chloride 1611 dropwise.

After the dropwise addition is completed, the temperature is gradually raised and stirring is continued at 60 to 70°C for 3 hours to complete the reaction.

After cooling to room temperature or below, the aqueous layer is separated and excess cyclopentylamine is distilled under reduced pressure and recovered.

After distillation, add 200ml of toluene to the residue and add 200ml of water.
Wash twice with water and dehydrate with anhydrous sodium sulfate.

Toluene was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain the target product, N-4-chlorobenzyl-cyclopentylamine 195.
v is obtained.

b, p, 109-b Synthesis Example 2 170 g of cyclopentylamine was maintained at 40°C with stirring, and 70'if of 4-methylbenzyl chloride was added dropwise.

After the dropwise addition was completed, the temperature was gradually raised and stirring was continued at 60°C for about 2 hours to complete the reaction.

Cool to about 15° C. and pour into a 400 ydO aqueous solution containing 24 g of sodium hydroxide.

After stirring thoroughly, the target product is extracted once with 300ml of toluene and twice with 100ml of toluene.

After dehydration over anhydrous sodium sulfate, toluene is distilled off under reduced pressure, and the residue is distilled under reduced pressure to obtain the target product, N-4-methylbenzyl-cyclopentylamine 911.

b, p, 102~103°C/0.3 MH? Typical examples of novel compounds synthesized by methods substantially similar to those described above are shown in Table 1.

Synthesis Example 3 By dissolving 4-chlorobenzylamine 141.5S' and cyclopentanone 84S' in 400 yd of toluene and gradually raising the temperature, water is immediately generated.
Azeotrope with toluene to completely remove water and complete the reaction.

After distilling off the toluene under reduced pressure, the condensate Schiff base is obtained.

Next, Schiff's base is dissolved in 300 yd of methyl alcohol, and 38 f of sodium borohydride is added dropwise under water cooling.

After completion of the dropwise addition, the mixture was stirred and reacted at 50° C. for 2 hours.

Methyl alcohol was distilled off from the reaction mixture under reduced pressure, the residue was diluted with water and the oil was extracted with ether.

The ether layer was dehydrated with anhydrous sodium sulfate, the ether was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain the target product N-4-
Chlorbenzyl-cyclopentylamine 150'? is obtained.

b, p, 109-110°C/0.27runH? The excellent effects of the urea or thiourea compounds obtained from the N-benzyl-cycloalkylamine compounds of the present invention can be recognized from the following test results conducted against various pathogenic bacteria.

Test Example 1 Control effect test on rice sheath blight (pot test) Preparation of test compound Active compound: 50 parts by weight Carrier: Mixture of diatomaceous earth and kaolin (1:5) 4
5 parts by weight Emulsifier: 5 parts by weight polyoxyethylene alkyl phenyl ether The above-mentioned amounts of the active compound, carrier and emulsifier are ground and mixed to form an aquarium, which is prepared by diluting the prescribed amount with water.

Test method Paddy rice (variety: Zennanfu) was cultivated in 1a15,000 Wagner pots in a submerged state, and during the panicle formation period, a diluted solution of the test compound at a predetermined concentration prepared as above was added to 100ml of water per 3 pots. It was distributed in proportion.

The day after spraying, the base of the test inn plants was inoculated with 100 ml of barley medium.
The sheath blight fungus that had been cultured for several days to form sclerotia was inoculated, and the temperature was increased to 2.
The plants were kept in a greenhouse at 8 to 30° C. and a relative humidity of 95 coefficients or higher for 10 days to develop the disease, and then the degree of disease onset and the presence or absence of phytotoxicity were investigated.

In the survey, the degree of damage was expressed based on the following criteria based on the growth of lesions from the inoculated site on the plant.

however, N: Total number of investigated stems no: number of disease-free stems nl: Number of stems with rice disease up to the first leaf sheath (from the bottom) n2 Number of stems with rice disease from the second leaf sheath (from the bottom) n3: Number of stems infected up to the third leaf sheath (from the bottom) or higher Table 2 shows the test results.

Note) 1. Polyoxin: polyoxin complex Table 29,
"-" for chemical damage indicates no chemical damage at all.

Test Example 2 Preparation of test compound for control effect test against Rhizopus seedling blight Active compound: 10 parts by weight Solvent Nidimethylformamide 80 parts by weight Emulsifier:
Polyoxyethylene alkyl phenyl ether 10 parts by weight Test method A mixture of Rhizopus oryzae cultured in bran medium for 5 days was inoculated into field soil sterilized in an autoclave (gray soil), and kept in a greenhouse for 48 hours to allow the bacteria to grow. It was used as an infected soil.

A seedling box for transplanting young seedlings (58 x 28 CIn) was filled with the above-mentioned infected soil to a thickness of 2 CrrL and flattened, soaked for 48 hours, and about 350 yards of germinated rice fir (variety: Asahi) was sown and covered with soil.

Then, add 500ml of diluted water solution to each seedling box.
Irrigate with a pipette and place in a greenhouse at 33-35°C for 4 hours.
I kept it for a day and allowed it to germinate.

The seeds were taken out of the greenhouse, greened and hardened using conventional methods, and then transferred to a greenhouse and seedlings were raised under normal management.

Fifteen days after sowing, 100 seedlings were removed from two locations in the center of the seedling box and classified into (A) severe disease, (B) mild disease, and (C) total disease according to root lesions and damping-off condition.

(A) Severe: withering or growth of the entire root or all crown roots is inhibited.

(B) One or two of the two mildly affected laminae and the seed plate are elongating normally.

(C) Healthy: Three or more shoe plates and seed plates are growing normally.

The degree of damage was calculated using the following formula.

)An double disease stem number Bn: Number of mildly affected stems Cn: Number of healthy stems N: An+Bn+Cn=100 The test results are shown in Table 3.

Note) ■, Daconyl: Tetrachloroinphthalonitrile, 75% hydrating powder 2, In the table, ``1-'' for drug damage indicates no signs of drug damage.

The present invention, which has been explained in detail in the detailed description of the invention, can be specifically summarized as follows.

(1) General formula (wherein R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R2 is a polymethylene group having 4 to 6 carbon atoms substituted by an alkyl group having 1 to 4 carbon atoms, or Substituted polymethylene group having 4 to 6 carbon atoms, X is a halogen atom,
It represents a nitro group, a cyano group, or an alkyl group having 1 to 4 carbon atoms.

) N-benzyl-cycloalkylamine compound represented by:

(2) General formula: (In the formula, R1 and X are the same as above.

Hal represents a halogen atom.

) benzyl halide represented by General formula: (In the formula, R2 is the same as above.

A method for producing an N-benzyl-cycloalkylamine compound represented by the general formula (I), which comprises reacting a cycloalkylamine represented by the following in the presence of an acid binder, if necessary: .

(3) General formula 2 (In the formula, R1 and X are the same as above.

) N-benzylamine represented by General formula: (In the formula, R2 is the same as above.

) by reacting with a cyclic ketone represented by General formula: (In the formula, R1, R2 and X are the same as above.

1. A method for producing an N-benzyl-cycloalkylamine compound represented by the general formula (0), which comprises producing a Schiff base represented by the following formula and then reducing the Schiff base.

Claims (1)

[Scope of Claims] 1 General formula: (wherein, R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R2 has 4 to 6 carbon atoms substituted by an alkyl group having 1 to 4 carbon atoms. a polymethylene group or an unsubstituted polymethylene group having 4 to 6 carbon atoms, X is a halogen atom,
It represents a nitro group, a cyan group, or an alkyl group having 1 to 4 carbon atoms. ) N-benzyl-dichloroalkylamine compound represented by: 2 R1 is a hydrogen atom or a methyl group, R2 is a tetramethylene group substituted with a methyl group or an unsubstituted tetramethylene group, X is a chlorine atom, a bromine atom,
Nitro group, cyanogen group or methoxy group. 2. The compound according to claim 1, which is a ru group. 3 R'' is a hydrogen atom or a methyl group, R2 is a pentamethylene group substituted with a methyl group, and X is a chloro atom, a bromine atom, a nitro group, a cyano group, or a methyl group, according to claim 1 4. The compound according to claim 1, wherein R'' is a hydrogen atom or a methyl group, R2 is a pentamethylene group, and X is a bromine atom. The compound according to claim 1, wherein SR" is a hydrogen atom or a methyl group, R2 is a -xamethylene group, and X is a chloro atom, a bromine atom, a nitro group, a cyano group, or a methyl group. Formula 6: N-4-chlorobenzyl-cyclopentylamine according to claim 1, represented by the following formula: N-4-brombenzyl-cyclopentylamine according to claim 1, represented by formula: 8: N-4-methylbenzyl-cyclopentylamine according to claim 1, which is represented by formula 9: N-4-chlorobenzyl-3-methylcyclopentylamine according to claim 1, which is represented by formula 9. 10 Formula: N-4-chloro-α-methylbenzyl-cyclopentylamine according to claim 1, represented by the formula: 11 N-4-nitrobenzyl according to claim 1, represented by the formula -cyclopentylamine. 12: N-4-cyanobenzyl-cyclopentylamine according to claim 1 represented by formula 1. 13 N-4-chlorobenzyl according to claim 1 represented by formula 2 -2-methylcyclohexylamine. Formula 14: N-4-bromobenzyl-2-methylcyclohexylamine according to claim 1, represented by: Formula 15: N-4-bromobenzyl-2-methylcyclohexylamine according to claim 1, represented by formula N-4-7'' lombenzyl-cyclohexylamine. 16 N-4-chlorobenzyl-cycloheptylamine according to claim 1, represented by formula 2. 17 General formula: (wherein, R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, X is a halogen atom, nitro group, cyan group, or an alkyl group having 1 to 4 carbon atoms, and Hal is a halogen atom) shows. ), and a benzyl halide represented by the general formula: A general formula characterized by reacting a polymethylene group with a cycloalkylamine represented by '), optionally in the presence of an acid binder: - (wherein R1, R2 and X are A method for producing an N-benzyl-cycloalkylamine compound represented by 18 General formula: (wherein, R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X is a halogen atom or a nitro group. , represents a cyano group or an alkyl group having 1 to 4 carbon atoms.N-benzylamine represented by the general formula: (wherein, R2 is the number of carbon atoms substituted by an alkyl group having 1 to 4 carbon atoms) 4-6 polymethylene group or an unsubstituted C4-6 polymethylene group.) By reacting with a cyclic ketone represented by the general formula: (wherein R1, R2 and N-benzyl represented by the general formula: (wherein R1, R2 and X are the same as above), which is characterized by producing a Schiff base represented by: - A method for producing a cycloalkylamine compound.