KR820001322B1 - Process for preparing tetrahydro-s-triazin-2(1h) thiones - Google Patents

Abstract

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Description

Method for preparing tetrahydro-S-triazine-2 [1H] -thione

The present invention relates to tetrahydro-S-triazine-2 [1H] -thione of the following structural formula (I) and acid addition salts thereof, which are effective as insecticides and acaricides.

In the above structural formula

R is alkyl, cycloalkyl, adamantyl, lower alkenyl or lower alkynyl group or substituted lower alkyl group (where the substituents are hydroxy, alkoxy, lower alkanoyloxy, carbamoyloxy, N-lower alkyl- Carbamoyloxy, N-cycloalkyl-carbamoyloxy, N-arylcarbamoyloxy, thiocarbamoyloxy, N-lower alkyl-thiocarbamoyloxy, N-cycloalkyl-thiocarbamoyloxy, N-aryl-thio Carbamoyloxy, aryl-sulfonyloxy, mono or lower alkylamino or aryl group.

R ¹ is lower alkyl or hydroxy methyl group

X is a hydrogen atom or a lower alkyl group.

The compounds of the present invention, tetrahydro-S-triazine thiones, are effective as pesticides and are particularly effective in eradicating ticks in one or more stages of growth, which are susceptible to the skin of animals such as sheep and cattle.

The compounds are also pesticidal against plant pests such as pea aphids.

Mites during all stages of growth tend to damage the skin of the animal and thus deteriorate the skin condition, thereby degrading the quality of the cows and lambs used in leather production. Moreover, ticks can affect animal health and affect the quality of the meat because of their transmission.

As used herein, the term "lower" used for a substitution group means up to 6 carbon atoms and the group containing 3 or more carbon atoms is straight or branched. When R is an alkyl group, it contains up to 12 carbon atoms. Halogen is fluorine, chlorine, bromine or iodine. Aryl is a phenyl group which may be optionally substituted from one or more halogen atoms or lower alkyl, lower alkoxy, trifluoromethyl, cyano or hydroxy groups.

Preferred groups of compounds according to the invention are those compounds of formula (I) in which X has a lower alkyl group, in particular a methyl group at the 4 position. Preference is also given to compounds of the formula (I) in which R ¹ is a lower alkyl group, in particular a methyl group and R is also a lower alkyl in particular methyl, isopropyl or -butyl group, or a cyclohexyl or hydroxyethyl group. Particularly preferred compounds of the present invention are as follows.

3- (2,4-dimethylphenyl) -1,5-dimethyl-tetrahydro-S-triazine-2 [1H] -thione, 3- (2,4-dimethylphenyl) -1-methyl-5-iso Propyl-tetrahydro-S-triazine-2 [1H] -thione and 3- (2,4-dimethylphenyl) -1-methyl-5-t-butyl-tetrahydro-S-triazine-2 [1H] -Tion.

The following compounds of formula (IA) are described in US Pat. Nos. 3,505,057 and 3,505,323 as herbicidal compounds, but the compounds of formula (I) having a methyl group at the 2-position of the phenyl group are not described. It is not mentioned that the structural formula (IA) compound is acaricide or insecticidal.

In the above structural formula

R ¹ is alkyl

R is alkyl, cycloalkyl, alkenyl, alkynyl or hydroxyalkyl

X is hydrogen or halogen

Y is hydrogen, halogen or alkyl.

The compound of formula (I) wherein R ¹ is lower alkyl can be prepared from substituted thioureas and amines (RNH ₂ ) of structure (II) in the presence of formaldehyde in the following manner.

In the above structural formula

R and X are as defined above

R ² is lower alkyl.

The reaction is usually carried out in an aqueous organic solvent (e.g. aqueous dioxane, aqueous propanol or aqueous ethylene glycol) and amine is added to the excess aqueous formaldehyde solution, followed by thiourea, preferably thiourea as a solution, Example: dioxane) can conveniently carry out the reaction. The reaction temperature is between room temperature and the reflux temperature of the solvent and takes several hours to several days to complete the reaction, depending on the nature of the reactants and the temperature used. The reaction is preferably carried out at 45 to 50 ° C. to prevent occasional decomposition and by-product formation at high temperatures, and it usually takes two to three days to actually complete the reaction at this temperature.

When R ² and R are lower alkyl groups (eg methyl groups) it is advantageous to carry out the reaction at high temperatures. In other words, it is heated on a steam bath, in which case the reaction is completed within 1 hour 30 minutes to 3 hours. In some cases, the solution is cooled to crystallize the product while the solvent is evaporated or vice versa by adding a large amount of water to the precipitate to conveniently separate the product and the product is filtered or extracted in an organic solvent (e.g. diethyl ether) Remove to collect product.

In either case, if necessary, the impure product can be further purified by conventional methods, i.e. recrystallization or chromatography.

The compound of formula (I) wherein R is a lower alkyl group substituted with a lower alkanoyloxy group can be prepared by acylating the corresponding hydroxy lower alkyl substituted compound with an acid chloride.

Structural formula (I) compounds wherein R is a lower alkyl group substituted with a carbamoyloxy, thiocarbamoyloxy or N-substituted carbamoyloxy or thio carbamoyloxy group are each potassium isocyanate or isotylocyanate or a suitable lower alkyl or cyclo Alkyl or aryl isocyanates or isothiocyanates can be used to make similar preparations from the corresponding hydroxy-lower alkyl substituted compounds.

Formula (I), wherein R is a lower alkyl group substituted with an aryl-sulfonyloxy group, can be prepared by sulfonylating the corresponding hydroxy-lower alkyl compound using sulfonylchloride.

The compound of formula (I) wherein R ¹ is hydroxy-methigroup can be prepared from the compound of formula (I) wherein R ¹ is hydrogen prepared as described above using thiourea of formula (II) wherein R ² is hydrogen. have. Thus, reacting with formaldehyde yields the compound of formula (I) wherein R ¹ is a hydroxy-methyl group.

Acid addition salts of compounds of formula (I) can be prepared by conventional methods. That is, the salt formed by precipitation is recovered by mixing a free base solution in a suitable solvent (eg diethyl ether) with a suitable acid (eg hydrochloric acid) solution in a suitable solvent (eg diethyl ether).

Thiourea of the structural formula (II) as a starting material is a known compound or can be easily prepared by a conventional reaction. For example, the preparation method of the compound of formula (II) wherein R ² and X are each methyl group is described in J. Chem. Soc., (1929) 945. Other compounds of formula (II) can also be similarly prepared by reacting aniline derivatives with appropriately substituted rings with alkylisothiocyanates. If necessary, the starting product, thiourea, can be obtained in a single step in which the impure reaction mixture is directly treated with formaldehyde and an amine of the formula RNH ₂ without the need for separation, thereby obtaining the final product of formula (I).

The amines of the structural formula RNH ₂ are all compounds that can be easily used.

Structural Formula (I) compounds include acaricides, particularly fertilized female mites, including Bophylus microplus, Haemaphysalis longicornus, and Lyphicephalus afendiculus Rhipicephalus appendi culatus and Boophilus decoloratus fertilize the ticks of various stages of growth.

In one test, acaricides were used for each of five Bupilose microplus mites before spawning. Using a micro pipepel, 10 μl of ethanol or acetone containing 10 μg of acaricide is sprayed onto the surface of each tick. The treated mite is placed in a 1 "x2" urine bottle, weighed and placed in a plastic box, placed under a condition of 26 ° C and a relative humidity of 80% for 2 weeks, and then the tick is removed from the bottle. Weigh the bottle and measure the weight of the tick spread. Scattering weights of untreated ticks were measured and the reduced scattering weight of treated ticks was calculated as a percentage.

The eggs that are laid are hatched again for three more weeks in the egg season to measure the hatching rate of eggs. The effect, expressed as a percentage, was calculated from the expected total hatching reduction of ticks using the egg weight and hatching rate. Repeat this test with a smaller amount of acaricide.

In another test, 0.5 ml pipette of a solution containing 0.5 mg of acaricide in ethanol or acetone was evenly sprayed on Whatman № 1 filter paper (8 cm × 6.25 cm) to a dose of 100 mg per m 2. The treated surface is left to dry and allowed to dry at room temperature, then the treated surface is folded in and the short edges are sealed using a crimping machine. A 1 Lb Killer bottle containing damp wet cotton wool is placed in a plastic foot, placed in a bag made of acaricide, and placed for 24 hours in an incubator at 26 ° C.

20 to 50 Bupphilus microplus larvae hatched from 8 to 14 days old are placed in the bag with a small spatula and sealed with a crimping machine. Place the larvae in a Killer bottle and leave for 48 hours in the incubation period.

As a control test, 20 to 50 larvae are placed in a bag made of untreated acaricide and operated as described above.

At 48 hours, larval mortality was recorded and expressed as a percentage after correction for the mortality in the untreated control trial.

Repeat this experiment with a smaller amount of acaricide. In terms of efficiency, the result for ED ₅₀ can be obtained from the capacity curve by the above test.

The effect on the Hemapisalis longgicornus pupa was measured by a method similar to the above larval test.

The acaricidal effect of the example compound against the Bifilus microfluidic mite is reported in the following table.

Table I Fertilization of Buphylus Microfluus (for topical use)

Accordingly, the present invention provides a composition having acaricide by mixing an effective amount of the compound of formula (I) with a diluent or carrier.

Diluents or carriers can be used as solids or liquids with antioxidants, dispersants, emulsifiers or wetting agents.

Compositions of the present invention include compositions in a form suitable for administration, as well as those compositions that can be supplied to a user and which are first concentrated to dilute with an appropriate amount of water or other diluent prior to administration.

Typical compositions of the invention include powders, dispersants, solutions, dispersions, emulsions and emulsions.

Powders can be made by mixing the appropriate amount of finely ground effective compounds with talc, clay, calcite, calcite, diatomaceous earth, appealing clamshell powder, solid powder diluents or carriers such as silica gel, hydrated alumina or calcium silicate. Another method is to mix the diluent or carrier with the active compound dissolved in a volatile organic solvent such as toluene and then evaporate to remove the solvent. Typically, the powder contains from 0.25 to 4% by weight of the active compound.

Particularly effective dispersants for sparging treatment are the addition of a suitable dispersant to the active compound or powder containing the active compound so that the powder and water are mixed to form a suitable aqueous dispersion of the active compound. It is preferable to contain 25 to 75 wt% of the effective compound in the dispersant.

Emulsions are solutions in which the active compound is dissolved in a water immiscible, nontoxic organic solvent containing an emulsifier. Suitable solvents include toluene, xylene, petroleum oils and alkylated naphthalenes. Preferred is when 5 to 75 g of active compound is contained per 100 ml of solution. Emulsions are diluted with water prior to use, with typical concentrations of the active compounds in the aqueous medium being 0.1% w / v (g / 100 ml) or approximately 100 to 100 p.m.

Volatile solvents (eg toluene and xylene) are evaporated after sparging, leaving only the precipitate of the active ingredient. Sprays or dipping solutions generally use emulsions.

The composition of the present invention can be used on land around dairy farms to control ticks of dairy cows. However, it is preferable to spray the animal directly or to treat it by dipping.

Therefore, the present invention provides a method of protecting an animal, in particular a cow, from a mite, especially a cow mite, by treating the outer surface of the animal with an astringent effective amount or a composition having an acaricide action, as described above.

The composition of the present invention may be an insecticide, a fungicide, acaricide and the like.

The invention is illustrated by the following examples.

Example 1

0.88 g (12 mmol) of t-butylamine is added dropwise to 20 ml of a cooled 37% formaldehyde solution with stirring. After 15 minutes, a solution obtained by adding 1.94 g (10 mmol) of N-2,4-dimethylphenyl N'-methylthiourea to 5 ml of dioxane was added and a solution was added thereto, and the mixture was then heated to 45 to 50 DEG C for 48 hours. The solvent is evaporated off under reduced pressure to give an oil which is washed with water and extracted twice with 50 ml of methylene chloride. The extracts are combined, dehydrated with magnesium sulfate and evaporated.

The residue is treated with 20 ml of diethyl ether and cooled to give crystalline precipitate. The precipitate was collected by filtration, washed with a small amount of cooled hexane and dried under vacuum to afford 5-t-butyl-1- (2,4-dimethylphenyl) -3-methyl-tetrahydro-S-triazine-2 [ 1H] -thione is obtained by white crystalline replacement.

Yield, 1.35 g (46%), melting point 111-112 ° C.

Elemental analysis: C ₁₆ H ₂₅ N ₃ S

Found: C 66.4%, H 9.0%, N 14.6%

Calculation: C 66.0%, H 8.6%, N 14.4%

m / e: found 291, calculated 291

Example 2

A solution of 121 g of 2,4-xylidine (purity 90%) in 195 ml of ethylene glycol was added to a mixture of 73 g of methyl isothiocyanate in 195 ml of ethethylene glycol over 5 minutes, and the mixture was stirred. Heat the bed for 30 minutes. 330 ml of formaldehyde 37% solution is added over 5 minutes followed by 230 ml of methylamine solution (25% W / V), then the reaction mixture is stirred again and heated for an hour and a half on a steam bath. The resulting clear solution is left to stir and cooled to room temperature to form a crystalline precipitate which is collected by filtration, washed with water and dried. Recrystallization from chloroform / hexanes affords 200 g (87% yield) of 1- (2,4-dimethylphenyl) -3,5-dimethyl-tetrahydro-S-triazine-2 [1H] -thione. Melting Point 107-108 ℃

Elemental Analysis: C ₁₃ H ₁₉ N ₃ S

Found: C 62.7%, H 7.7%, N 17.0%

Calculated Value: C 62.3%, H 7.6%, N 16.9%

m / e: found 249, calculated 249

Example 3-20

The following tetrahydro-S-triazine-2 [1H] -thione is prepared according to the method of Example 1 with suitable thiourea and amine as starting materials.

Example 21

4.86 g (37% solution, 30 mmol) of formaldehyde is added to a solution of 4.5 g (24 mmol) of 2,4-dimethyl-phenylthiourea in 40 ml of dimethylformamide and stirred at room temperature for 15 minutes. 3.72 g (30 mmol) methylamine is added dropwise with stirring and the mixture is heated at reflux at 100 ° C. for 4 hours. Cooling the solution and removing the solvent under vacuum produces oil. The oil is diluted with diethyl ether and cooled to afford 1- (2,4-dimethylphenyl) -5-methyl-tetrahydro-S-triazine-2 [1H] -thione as a white crystalline solid. This crystalline solid was collected by filtration, washed with a small amount of cooled diethyl ether and dried to yield 4.5 g (77%). Melting Point: 140 ~ 143 ℃

1.18 g (5 mmol) of the product is dissolved in 5 ml of dioxane while warming, the solution is cooled to room temperature and 0.41 g (37% solution, 5 mmol) of formaldehyde is added. The solution is kept at 45 ° C. for 6 hours. After the solvent was removed in vacuo, the product was washed with water, dissolved in dichloromethane, dehydrated with magnesium sulfate, and the solvent was evaporated to give a clear oil which was solidified by stirring with 50 ml of diethyl ether.

The product was recrystallized from a mixture of hexane and dichloromethane to white crystallize 1- (2,4-dimethylphenyl) -3-hydroxymethyl-5-methyl-tetrahydro-S-triazine-2 [1H] -thione. Obtained as a sexual solid.

Yield: 0.40 g (30%), Melting point: 121-122 ° C

Elemental Analysis: C ₁₃ H ₁₉ N ₃ OS

Found: C 58.5%, H 7.1%, N 15.65%

Calculated Value: C 58.9%, H 7.2%, N 15.85%

Example 22

0.168 g (1.5 mmol) of acetyl chloride and 1- (2,4-dimethylphenyl) -5- (2-hydroxymethyl) -3 in 45 ml of anhydrous toluene containing 0.3 g (3 mmol) of triethylamine -Methyl-tetrahydro-S-triazine-2 [1H] -thione was added dropwise with stirring to the cooled solution to which 0.60 (1 mmol) was added. After 10 minutes, the solution is allowed to warm to room temperature and then stirred for another 3 hours. After filtering the solution the solvent is removed in vacuo. The product is chromatographed on silica gel column with 2% methanol and dichloromethane as eluent to afford an oil. 0.24 g (35%) of 5- (2-acetoxyethyl) -1- (2,4-dimethylphenyl) -3-methyl-tetrahydro-S-triazine-2 [1H] -thione when treated with diethyl ether You get Melting Point: 80 ~ 83 ℃

Elemental analysis: C ₁₆ H ₂₃ N ₃ O ₂ S

Found: C 59.7, H 7.3, N 12.95%

Calculated Value: C 59.8, H 7.2, N 13.1%

Example 23

1- (2,4-dimethylphenyl) -3-methyl-5- (2-pivaloyloxyethyl) -tetrahydro-S-triazine-2 according to the method of Example 22 using pivaloyl chloride [1H] -thione is obtained as an oil.

Elemental Analysis: C ₁₉ H ₂₉ N ₃ O ₂ S

Found: C 62.35%, H 8.1%, N 10.9%

Calculated Value: C 62.8%, H 8.0%, N 11.6%

Example 24

0.62 g (5.2 mmol) of phenyl isocyanate was added to 40 ml of anhydrous toluene in 1- (2,4-dimethylphenyl) -5- (2-hydroxyethyl) -3-methyl-tetrahydro-S-triazine-2 [ 1.0 g (3.5 mmol) of 1H] -thione and 0.31 g (5.2 mmol) of triethylamine are added to the solution with stirring, and the mixture is stirred at room temperature for 2 hours. The gum residue obtained by removing the solvent in vacuo was treated with petroleum ether (boiling point 60 to 80 ° C.) to give 1- (2,4-dimethylphenyl) -3-methyl-5- (2-N-phenyl-carbamoyloxyethyl ) -Tetrahydro-S-triazine-2 [1H] -thione is obtained.

Yield: 1.18 g (84%)

Melting Point: 60-65 ℃

Elemental Analysis: C ₂₁ H ₂₆ N ₄ O ₂

Found: C 64.0%, H 6.6%, N 13.5%

Calculated Value: C 63.3%, H 6.5%, N 14.1%

Example 25

1- (2,4-dimethylphenyl) -3-methyl-5- (2-N-methyl-carbamoyloxyethyl) -tetrahydro-S-triazine- according to the method of example 24 using methylisocyanate 2 [1H] -thione is obtained.

Use point: 110 ~ 113 ℃

Elemental Analysis:

Found: C 57.0%, H 7.2%, N 16.8%

Calculated Value: C 57.1, H 7.1%, N 16.7%

Example 26

1.0 g (3.6 mmol) of 1- (2,4-dimethylphenyl) -5- (2-hydroxyethyl) -3-methyl-tetrahydro-S-triazine-2 [1H] -thione in 10 ml of dimethylformamide Molar) is slowly added to 0.172 g (3.6 mmol, 50% dispersion in oil) of sodium hydride suspension at room temperature. When hydrogen gas generation is stopped, a solution of 0.74 g (5.3 mmol) of cyclohexyl isocyanate is added to 5 ml of dimethylformamide, and the mixture is stirred at room temperature for 3 hours. The solution is poured into 50 ml of water and the product is extracted with ether. The ether layer is separated, washed with water, dehydrated and the solvent is removed to give an oil. When treated with petroleum ether (boiling point 60 to 80 ℃)

Produced as 1- (2,4-dimethylphenyl) -3-hydroxymethyl-5-methyl-tetrahydro-S-triazine2 [1H] -thione white solid. Yield: 0.18 g (12%), Melting point: 168 to 72 ° C

Elemental Analysis: C ₂₁ H ₃₂ N ₄ OS ₂

Found: C 59.8%, H 7.7%, N 13.1%

Calculated Value: C 60.1%, H 7.4%, N 13.4%

Example 27

Obtained according to the method of Example 26 using methylisothiocyanate.

Melting Point: 80 ~ 90 ℃

Elemental analysis: C ₁₆ H ₂₄ N ₄ OS ₂

Found: C 55.1%, H 7.0%, N 15.3%

Calculated Value: C 54.5%, H6.8%, N15.9%

Example 28

Obtained according to the method of Example 26 using phenylisothiocyanate.

Melting Point: 64 ~ 70 ℃

Elemental Analysis:

Found: C 61.6%, H6.3%, N 13.7%

Calculated Value: C 60.9%, H 6.3%, N 13.5%

Example 29

A solution of 3.0 g of P-toluene sulfonyl chloride in 5 ml of pyridine is poured into 400 ml of water dissolved in 1.5 ml (1.8 mmol) of 10 ml of pyridine, and all the eggs are extracted. The product is extracted twice with 100 ml of ether. The combined etheric extracts are washed with dilute hydrochloric acid and water and dehydrated. The residue of the gum removed from the solvent is treated with ethyl acetate. Cool the solution and slowly add petroleum ether (boiling point 40 to 60 ° C) to give a white solid.

Porosity: 0.9 g (585), melting point; 82 to 85 ℃

Elemental analysis: C ₂₁ H ₂₇ N ₃ S ₂ O ₃

Found: C 58.4%, H 6.3%, N 9.6%

Calculated value; C 58.2% H 6.2%, N 9.7%

Example 30

3.6 g (4 mmol) of aqueous formaldehyde was added to 500 mL of ethylene glycol, followed by the addition of N-2,4-dimethylphenyl-N'-ethyl-thiourea 1.94 g 9 (mmorimol), followed by N to a small amount of ethylene glycol. A solution of 1.76 g (2 mmol) of N-dimethyl-ethylenediamine was slowly added. The mixture is heated at 80-90 ° C. for one hour, then cooled and poured into water. The product is extracted into ether, the ether layer is separated, washed with water and evaporated to dryness.

The impure product was chromatographed on a silica gel column with dichloromethane containing 3% methanol as eluent to give an oil which was solidified by treatment with petroleum ether (boiling point 40 to 60 ° C.) to give 0.6 g (20%). . Melting Point: 65 ~ 70 ℃

Elemental Analysis: C ₁₆ H ₂₆ N ₄ S

Found: C 62.25%, H8.6%, N 17.8%

Calculated Value: C 62.7%, H8.5%, N 18.3%

Example 31

The hydrogen chloride solution added to the ether is added to an ether solution of 1 (2,4-dimethylphenyl) -3,5-dimethyl-tetrahydro-S-triazine-2 [1H] thion. The cooked rice is left in a cold place for 1 hour to collect the precipitated hydrochloride, washed with a small amount of cold ether and dried. Melting Point: 164 ~ 165 ℃

Elemental Analysis: C ₁₃ H ₁₉ N ₃ S HCI

Found: C 54.45%, H 7.6%, N 15.25, CI 12.6%

Calculated Value: C54.6%, H 7.0%, N 14.7%, CI 12.4%

Claims (1)

The thiourea of formula (II) is reacted with an amine of formula RNH _{2 in} the presence of formaldehyde to form tetrahydro-S-triazine-2 [H] -thione of formula (I) How to make

In the above structural formula R is an alkyl, cycloalkyl, adamantyl, lower alkenyl or lower alkynyl group substituted lower alkyl group Wherein the substituents are hydroxy, alkoxy, lower alkanoyloxy, carbamoyloxy, N-lower alkyl-carbamoyloxy, N-cycloalkyl-carbamoyloxy, N-arylcarbamoyloxy, thiocarbamoyloxy, N Lower alkyl-thio-carbamoyloxy, N-cycloalkyl-thiocarbamoyloxy, N-aryl-thiocarbamoyloxy, aryl-sulfonyloxy, mono or lower alkyl amino or aryl group; R ¹ is lower alkyl or hydroxy methyl group R ² is hydrogen or a lower alkyl group X is a hydrogen atom or a lower alkyl group.