KR810001411B1 - Process for preparing tetrahydro-1,3,5-thiadiazin-4-one derivative - Google Patents

Abstract

Fungicidal title compds. (I; R1,R2,R3 = C1-8 alcohol; aryl, C3-6 cycloalkyl, C3-6 alkoxyalkyl, benzyl, phenyl, substituted phenyl, or R1 = hydroxyphenyl, R2 = H, furfural, R3 = H) were prepd. by reaction of carbamoylchloride(II) and thiourea(III) in the presence of base. Thus, 3.4 g(0.02 mol) II(R1 = iso-C3H7) in 50 ml C6H6 and 3.3 g(0.02 mol) III(R2 = -C6H5; R3 = Me) were stirred for 2 hr under refluxing, filtered, washed, extracted with C6H6, and recrystallized with isopropylalcohol to give 2.1 g(40%) I (R1 = iso-C3H7; R2 = -C6H5; R3 = Me).

Description

Method for preparing tetrahydro-1,3,5-thiadiazin-4-one derivative

The present invention is the following general formula

(Wherein, R ^1, R ² and R ³ are good may be the same or different from each other, and each of C ₁ -C ₈ al kalgi, an allyl group, a cycloalkyl group, a total of 3 to 6 carbon atoms in the C ₃ -C ₆ An alkoxyalkyl group, a benzyl group or a substituent having one or two alkyl groups of C ₁ -C ₄ , a nitro group, a halogen atom, an alkoxy group having an alkoxy group of C ₁ -C ₄ , or a substituted phenyl group having a trifluoromethyl group R ¹ may represent a hydroxy phenyl group, R ² may represent a hydrogen atom, and furfuryl group R ³ may represent a hydrogen atom.

Tetrahydro-1,3,5-thiadiazine-4- represented by the present invention relates to a method for producing a derivative. The present invention also relates to pesticides and tick control agents containing a compound represented by the above general formula or an acid addition salt thereof as an active ingredient.

The compound represented by general formula (I) and its acid addition salt are novel compounds.

The compound represented by said general formula (I) is the following general formula

(Wherein R ¹ is the same as described above)

Carbamoyl chloride represented by the following general formula in the presence of a base

Wherein R ² and R ³ are the same as described above.

It can be synthesize | combined easily by reacting with the thiourea represented by. This reaction can be represented by the following reaction formula, and the compound of general formula (I) can be obtained in free state.

Wherein R ¹ , R ² and R ³ are the same as described above.

On the other hand, carbamoyl chloride of general formula (II) and thiourea of general formula (III) can be reacted without adding a base. In this case, the compound of general formula (I) is obtained in the form of hydrogen chloride. This reaction is advantageously carried out under heating conditions. Therefore, when it is necessary to obtain the compound of general formula (I) in the form of hydrogen chloride, it is usual to react by this method. When it is necessary to obtain the compound of general formula (I) in a free state, hydrogen chloride is dissolved in water and obtained by adjusting the pH of this solution to neutral or weakly alkaline. This reaction can be represented by the following equation.

Therefore, the compound of general formula (I) can be synthesize | combined by either method of A or B method. The compound of formula (I) can also be converted to its salt by conversion to a suitable acid. All of these methods fall within the scope of the present invention.

Carbamoyl chloride used as one of the reactants of the present invention can be synthesized, for example, by the following or similar methods.

The method (4) and (5) above is an improvement of the method (2) by the present inventors.

(1) The method cannot be used for chlorination of an aniline derivative having a substituent sensitive to chlorination in its benzene nucleus. In such a case, it is necessary to further perform an addition reaction, and in this addition reaction, the dehydration-concentration product of the aniline derivative and the surface aldehyde (e.g., azomethine or hexahydro-S-triazine) is added to the above-mentioned (2)- Reaction with phosgene or trichloromethylchloroformate as shown in method (5). The resulting carbamoyl chloride need not be isolated, but the reaction mixture can be used in the next reaction to react with thiourea.

As a result of careful study by the present inventors, several important features of the ring-forming reaction of the present invention have been revealed. When the substituents in the diurea molecule are different, the positions occupied by the substituents R ² and R ³ in the final compound of the general formula (I) tend to be assured. When both R ² and R ³ of the thiourea are alkyl groups, the substituents occupying the R ³ position in the compound (1) are generally alkyl groups having long carbon chains or large alkyl groups having more carbon side chains at the nitrogen atom, The macroalkyl group is preferred to the chain group of. Thus, when using 1,3-dialkyl-thiourea having a linear alkyl group, an alkyl group having a greater number of carbon atoms occupies the position of the compound of formula (I). When using thiourea having almost the same substituents as the above-mentioned large reactors, mixtures of compounds having the following structural formulas are often formed.

(Wherein Alk ¹ and Alk ² represent alkyl groups having almost the same degree of branching). In this regard, the phenylalkyl group exhibits a tendency similar to that of the alkyl group.

In the case of carrying out the cyclization reaction using 1-alkyl-3-arylthiourea, an aryl group is introduced at the R ² position of compound (I). However, even when using thiourea in this way, when the alkyl di group is a methyl group, a mixture of compounds (I) having a methyl group at the R ² position and a methyl group at the R ³ position is often obtained.

This mixture can optionally be separated into both compounds using solubility differences.

Representative examples of the mixture obtained are shown below.

As mentioned above, it is important that the cyclization reaction of the present invention is related to the enlarging of the steric structure of R ² and R ³ .

The raw material compound represented by general formula (II) and (III) is demonstrated later. R ¹ , R ² and R ³ are as defined above. Alkyl groups having from 1 to 8 carbon atoms are straight and branched chain alkyl groups, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-butyl, n-pentyl, 3 -Methylbutyl, n-hexyl, heptyl, n-octyl, 1,1,3,3-tetramethylbutyl (-octyl), 2-ethylhexyl group, etc. are mentioned. And ethoxycyclohexyl, cyclopentyl, cyclopropyl and cyclobutyl groups of cycloalkyl groups having 3 to 6 carbon atoms. Examples of the alkoxy alkyl group each having 3 to 3 carbon atoms as a whole include methoxyethyl, methoxypropyl, ethoxyethyl, propoxyethyl and butoxyethyl groups.

In the substituted phenyl group represented by R ¹ , R ² and R ³ , which may be the same as or different from each other, the halogen substituent is fluorine, chlorine, cancelled and oxo, and is linear and condensed with a substituent of an alkyl or alkoxy group having _{1 to 4} carbon atoms. You can lift the flag. Representative examples of the substituted phenyl group include chlorophenyl, dichlorophenyl, fluorophenyl, methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, trifluoromethylphenyl, chlorotolyl, chloromethoxyphenyl, tolyl, and dimethylphenyl group. .

The reaction of the present invention is suitably carried out in a solvent in which the reaction does not seriously impede the progress. Suitable solvents for use in the reaction of the present invention include water: aromatic hydrocarbons such as benzene, toluene and xylene; Acetone, cyclohexanone, methyl ethyl ketone, etc. are ketones; Ethers such as tetrahydrofuran, dioxane and ethyl ether; Halogenated hydrocarbons such as chloroform, carbon tetrachloride and chlorobenzene; Alcohols such as ethanol and propanol; Esters of aliphatic acids such as ethyl acetate; Aliphatic amides such as dimethylformamide and dimethylacetamide; Dimethyl sulfoxide and other solvents that do not significantly affect the reaction of the present invention. These solvents can also be used in admixture with mixtures of water and organic solvents and mixtures of organic solvents.

Examples of bases that can be used in the reaction of the present invention include inorganic bases such as potassium hydroxide, sodium hydroxide, aqueous ammonia solution, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; Organic bases such as triethylamine, pyridine and 1,8-diazabicyclo 5,4,0-7-undecene. In most cases, these bases are used in the form of aqueous solutions, even in powder form.

The reaction temperature may be used within the range of -10 ° C to 200 ° C, but a suitable temperature range is from room temperature to about 100 ° C for the method (A) and 60 ° C to 130 ° C for the method (B).

Since thiourea and N-chloromethyl-N_phenylcarbamoyl chloride are equimolar, the reactants are used in equimolar ratios or in slightly higher amounts than either reactant. The amount of base used for 1 mole of any component of the reactants is 2 moles or slightly more for the method (A) and 1 mole or slightly more for the method (B).

After completion of the reaction, the reaction mixture is treated with a suitable solvent to extract the compound of formula (I), the extract solution is washed, dried and liberated from the solvent to obtain compound (I) in crystalline or oily phase, as necessary. Further purified.

When the compound of formula (I) is to be recovered in the form of a salt, the method (B) is carried out or the compound (1) is treated with a suitable acid. To acids used for producing _{salt, HC1, HBr, H 2 SO} 4, H 3 PO 4, NHO 2, HC1O 4, CH 3 COOH, CC 3 COOH, the acid and benzene sulfonic acid with the usual inorganic or organic acid containing the Can be used.

Representative examples of general formula (I) are shown below.

Compounds of formula (I) exhibit potent physiological activity against insects, in particular larvae. Larvae that have been treated with this compound or larvae that have eaten worms treated with this compound will die abnormally. Examples of insects sensitive to compound (I) include Hemiptera, Coleoptera, Dipteria, Lepidoptera and Orthoptera. In addition, most of the compounds of the general formula (I) have an insecticidal effect on ticks, and some of them have mortality of more than 80% at concentrations of 1000 ppm for Panonychus citri McGregor and Tetranychs Urticac Koch. Tick mechanism effect was shown. Thus, the compounds of the present invention can be used as physiologically effective substances for controlling pests by using them on parts of plants, grains and other plants to prevent damage caused by insects and mites described above.

For example, the compounds of the present invention are effective in preventing pest damage to rice, corn and other cereals, vegetables, flowers and ornamental plants, trees, cotton, fruit trees, forests, harvested grains, grasses, grasses and wood products. Can be used as a substance. This compound is also useful for controlling pests that are unnecessary to the living environment, such as mosquitoes and flies. This compound is especially used for controlling pests in rice fields such as Nilaparvata lugens Stal, Laodelphax striatellus Fall'en, Sogatella furcifera Horvath, Nephotettix cincticeps Uhler and other extinct pests and cicadas. Particularly useful.

In addition, compared to conventional insecticides such as phosphorus compounds and carbamate compounds, the compounds of the present invention have a much lower acute toxicity in leuko mammals and are therefore much safer. For example, 2-t-butylimino-3-isopurophyll-5-phenyltetrahydro-1,3,5-thiadiazin-4-one (Compound No. 145 and 2-t-butylamino- 3-Isopropyl-5-P-tolyltetrahydro-1,3,5-thiadiazin-4-one- (compound No. 318) had an LD ₅₀ of 10000 mg / kg or more (cub, male). Many other compounds of the invention had an LD ₅₀ (mice, male) of more than 5,000 mg / kg. Compared with conventional phosphorus and carbamate insecticides, the compounds of the present invention have a pesticidal effect depending on the specific pests desired. Although the pesticide effect is changed, the insecticide is exhibited at low concentrations, for example, 1-naphthyl N-methylcarbamate (commercial insecticide) when mortality was compared 7 days after the compound was administered to the larvae of the fifth larva stage. NAC) showed a mortality rate of only 30% at 200 ppm, while compounds of the invention, for example 145 or 318, exhibited a mortality rate of 100% at 100 ppm concentration. Found.

The present invention also provides a method for eradicating or controlling pests and ticks based on the physiological effects of the compounds of the present invention. In one embodiment of the present invention, the compound may be used directly on the target to be protected or the pest to be controlled (sprayed without dilution). For example, a compound of the present invention in the form of a liquid having a purity of at least 95% can be sprayed from an airplane and sprayed in the form of extremely fine liquid particles. The compounds of the present invention may also be toxic to the larvae by administering them to ponds and puddles where the larvae live or by treating the surrounding water or irrigation water to grow the host.

However, as is known in the art, the compounds of the present invention are, in most cases, used in a form suitable for use by diluting with an inert sugar or diluting with an inert sugar, or by admixing with an adjuvant as necessary The physiological effect of this eradicates or controls pests and ticks.

Methods relating to the preparation of pesticides based on the compounds of the invention are described below. The compound of the present invention is mixed with a suitable amount of a suitable inert sugar and an adjuvant as necessary to dissolve, disperse, suspend, mix, saturate, absorb or adsorb the solution, suspending agent, emulsifying thickener, oil spraying agent, hydrating component, powder, granule It may be formulated into a suitable formulation such as tablets, pills, pastes or aerosols.

Inert sugars are solid, liquid or gaseous. Examples of solid sugars include plant powders such as soy flour, grain flour, wood flour, bark flour, sawdust, sugar pear stem powder, walnut shell powder, bran, powdered cellulose and extracts of other plants; Fibrous materials such as paper, creased fibreboard and waste cloth; Synthetic polymers such as powdered synthetic resins and polymer particles (eg, urea-formaldehyde polymers); Clay (e.g. solid soil, bentonite and acidic clay), siliceous material (e.g. diatomaceous earth, silica sand, mica, synthetic silicate, milled synthetic silicic acid, etc.), powdered sulfur, activated carbon, pumice, calcined diatomaceous earth, brick mill, Powders such as volcanic ash, sand, calcium carbonate and calcium phosphate or particulate inorganic or minerals of suitable particle size; Chemical notes such as ammonium sulfate, ammonium phosphate, ammonium nitrate, urea and ammonium chloride; Artificial mixed fertilizers, sodium sulfate, sugars and other soluble substances.

These solid sugars may be used alone or in combination of two or more. The liquid sugar substance is selected from nonsolvents capable of dispersing the active ingredient in the presence of an appropriate auxiliary agent as well as a solvent for the active ingredient.

Such liquid sugars may be used alone or in combination of two or more thereof. Examples include water, alcohols (e.g. methanol, ethanol, butanol and ethylene glycol), ketones (e.g. acetone, methyl ethyl ketone, diisobutyl ketone and cyclohexanone), ethers (e.g. ethyl ether, di Oxane, cellosolve, dipropylether and tetrahydrobutane), aliphatic dehydrogenated hydrogen (e.g. gasoline and mineral oil), aromatic hydrocarbons (e.g. benzene, xylene, solvent naphtha and alkylnaphthalane), halogenated hydrocarbons (e.g. dichloroethane , Chlorobenzene and tetrachloride hydrocarbons, esters (e.g. ethyl acetate, dibutylphthalate and dioctylphthalate), acid amides (e.g. dimethylformamide, diethylformamide and dimethylacetamide), nitriles (e.g. Acetonitrile), dimethyl sulfoxide, and the like. Examples of gaseous sugars include freon and other aerosol sprays which are gases under normal conditions.

Examples of adjuvants may include the following substances, depending on the intended use. Often, more than one adjuvant is used in combination, in some cases no adjuvant is used at all. Surfactants are used to emulsify, disperse, dissolve and / or hydrate the active ingredients. Examples of surfactants include polyoxyethylene alkylaryl ethers, polyoxyethylene alkyl ethers, polyoxyethylene higher fatty acid esters, polyoxyethylene resin acid esters, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monooleates, alkyls Arylsulfonates, naphthalenesulfonic acid condensates, ligninsulfonates and higher alcoholsulfate esters. The following materials are used as dispersion stabilizers, electrodeposition agents and binders for the active ingredients: casein, gelatin, starch, alginate, methylcellulose, carboxymethylcellulose, gum arabic, polyvinyl alcohol, dry distilled wood terbin, rice bran oil, bentonite And ligninsulfonate.

In order to increase the fluidity of the solid preparation, waxes, stearates and alkylphosphenines can be used. Naphthalenesulfonates and polyphosphates are used as dispersing pectifying agents. Antifoaming agents such as silicone oils may also be used in the formulations.

The proportion of the active ingredient in the extracting agent may be cotton as desired. The proportion of the active ingredient is generally 0.5 to 20% by weight in the case of powder or granules, and 0.1 to 90% by weight in the case of emulsifiers and hydration components.

In order to exterminate various pests or to protect plants from pest damage, the pesticides of the present invention are suitably diluted and suspended in water or other media, and an effective amount of the preparation is placed on or around the plant or in areas where the pests live. Used for For example, in order to control pests inhabiting rice fields, the insecticide of the present invention is used on the foliar and stem of rice, or in the soil of rice paddies or water accumulated in rice fields.

The rate of use of the pesticide of the present invention varies depending on various factors, for example, the type of insect desired, the state and tendency of the appearance of pests, the climate, the environmental conditions, the form of the pesticide, the type of use, the place of use and the season. In general, in the case of emulsifying and hydrating powders used in liquid form, it is customary to dilute the final concentration of at least 0.001% by weight of the active ingredient to prepare a spray agent. Powders and granules are generally used at a rate of 1 to 10 KG per 10 liters. However, the above use ratio does not limit the scope of the present invention.

The pesticides of the present invention may be mixed with or used with other insecticides, fertilizers, plant nutrients and plant growth regulators as needed. Examples of pesticides that can be used in combination with the pesticides of the present invention may include the following.

0,0-dimethyl 0- (4-nitro-3-methylphenyl) thiophosphate (Phenitrocthion)

0,0-dimethyl 0- (3-methyl-4-methylthiophenyl) thiophosphate (Baycid)

0,0-dimethyl S- (carbethoxyphenylmethyl) dithiophosphate (Elsan)

0,0-diethyl 0- (2-isopropyl-4-methylpyrimidyl-6) thiophosphate (Diazinon)

0,0-dimethyl 2,2,2-trichloro-1-hydroxyethylphosphonate (Dipterex)

0-ethyl 0-P-cyanophenylphenylphosphothioate (Surecide)

0-ethyl 0-P-nitrophenylthiophosphonoate (EPN)

P, P-dipropyl 0-4-methylthiophenylphosphate (Propaphos)

0,0-dimethyl S-phthalamidomethyldithiophosphate (Imidan)

0,0-dimethyl 0-dichlorovinylphosphate (DDVP)

0,0-dimethyl S- (N-methylcarbamoylmethyl) dithiophosphate

0,0-dimethyl S- (1,2-dicarboethoxyethyl) dithiophosphate (malathon)

1-naphthyl N-methylcarbamate (NAC)

m-tolyl N-methylcarbamate (MTMC)

2-isopropoxyphenyl N-methylcarbamate (PHC)

Ethyl N- (diethyl-dithiophosphoacetylacetyl) -N-methylcarbamate (Mecarbam)

3,4-xylyl N-methylcarbamate (MPMC)

2-butylphenyl N-methylcarbamate (BPMC)

2-isopropylphenyl N-methylcarbamate (MIPC)

2-chlorophenyl N-methylcarbamate (CPMC)

3,5-xylin N-methylcarbamate (XMC)

2- (1,3-dioxolan-2-yl) phenyl N-methylcarbamate (Dioxacarb)

3-t-butylphenyl N-methylcarbamate (Terbam)

4-diallylamino-3,5-dimethylphenyl N-methylcarbamate (APC)

S-methyl-N- (methylcarbamoyloxy) thioacetoimimate (Methomil)

N- (2-methyl-4-chlorodimethyl) -N, N-formamidine hydrochloride (Chlorphenamidine)

1,3-bis (carbamoylthio) -2- (N, N-dimethylamino) -propanehydrochloride (Cartap)

Diisopropyl-1,3-dithiolane-2-ylidenemalonate (Isoprothiolan)

-[(4-chlorophenyl) aminocarbonyl] -2,6-difluoro benzamide (Diflubenzuron)

0,0-dimethyl-S- [2- (isopropylthio)] ethylphosphorodithioate (Isothiate)

0,0-diethyl-S- [2- (ethylthio) ethyl] -phosphorodithioate (Disulfoton)

2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methylcarbamate (Carbofuran)

Example 1

2-Methylimino-3-phenyl-5-isopropyltetrahydro-1,3,5-thiadiazin-4-one (Compound No. 66):

In 50 ml of benzene, 3.4 g (0.02 mol) of N-isopropyl-N-chloromethylcarbamoyl chloride and 3.3 g (0.02 mol) of 1-methyl-3-phenylthiourea were dissolved. The resulting solution was stirred at reflux for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with benzene and dissolved in 200 ml of water. The resulting aqueous solution was mixed with 20 ml of saturated aqueous sodium carbonate solution and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated under reduced pressure to give crystals which were recrystallized from isopropyl alcohol.

Melting point: 174 to 176 ° C; Quantity 2.1g (40%)

NMR (CDC1 ₃ ) δ: 1.19 (d.6H), 3.00 (S.3H), 4.42 (S.2H) 4.30-4.80 (m.1H), 7.0-7.6 (m.5H)

Example 2

2-p-tolylimino-3-methyl-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 72)

In 50 ml of toluene, 3.7 g (0.02 mol) of N-t-butyl-N-chloromethylcarbamoyl chloride and 3.6 g (0.02 mol) of 1-methyl-3-p-tolylthiourea were dissolved. The resulting solution was heated at reflux for 2 hours. The precipitated crystals were collected by filtration and washed with acetone (189-190 DEG C, decomposition). This crystal was dissolved in 100 ml of water, mixed with 10 ml of 20% sodium hydroxide solution, and extracted with 50 ml of benzene. The crystals obtained by removing benzene under vacuum were recrystallized from isopropyl alcohol. Yield 4.3 g (73%); Melting Point 113 ~ 115 ℃

NMR (CDC1 ₃ ) δ: 1.48 (S.9H), 2.30 (S.3H), 3.35z (S.3H), 4.48 (S.2H), 6.65-7.25 (m.4H)

In a similar way, the following general expression

2- (2-Methyl-4-chloro) -phenylimino-3-methyl-5-isopropyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 67) Was obtained from 3.4 g of N-isopropyl-N-chloromethylcarbamoylchloride and 4.2 g of 1-methyl-3- (2-methyl-4-chloro) phenylthiourea. Melting point 91 to 92 ° C; Quantity 3.2g.

NMR (CDC13) δ: 1.20 (d.6H), 2.10 (S.3H), 3.45 (S.3H), 4.30 (S.2H), 4.45-4.95 (m.1H), 6.55-7.20 (m.3H )

Example 3

2-t-butylamino-3-phenyl-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4-silver (Compound No. 77)

In 50 ml of acetone, 3.7 g (0.02 mol) of N-t-butyl-N-chloromethylcarbamoyl chloride and 3.9 g (0.02 mol) of 1-t-butyl-3-fethiourea were dissolved. On the other hand, 2.8 g of powdered potassium carbonate was added to the resulting solution while stirring. Then heated at reflux for 2 hours. The reaction mixture was poured into water and extracted with 50 ml of benzene. The benzene layer was washed with water, dried and concentrated under reduced pressure. The obtained crystals were recrystallized from isopropyl alcohol. Yield 4.1 g (66%); Melting point 133-134 degreeC.

NMR (CDC1 ₃ ) δ: 1.10 (S.9H), 1.46 (S.9H), 4.60 (S.2H), 7.0-7.4 (m.5H)

Example 4

2-ethylimino-3-0-tolyl-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 80);

In 50 ml of benzene, 3.7 g (0.02 mol) of N-t-butyl-N-chloromethylcarbamoyl chloride and 3.8 g of 1-ethyl-3-0-tolylthiourea were dissolved. While stirring, on the other hand, 8g of 20% sodium hydroxide aqueous solution was added to the said solution, and stirring was continued at 30-50 degreeC for 4 hours. The reaction mixture was poured into water and extracted with 50 ml of benzene. The benzene layer was washed with water and dried. The benzene layer was washed with water and dried. The crystals obtained by removing benzene by distillation were recrystallized from isopropyl alcohol. Yield 3.8g (63%), melting | fusing point 157-158 degreeC.

Example 5

2-phenylimino-3-phenyl-5-t-butyl-petrahydro-1,3,5-thiadiazine-4-silver (compound No. 78)

In a mixture of 50 ml of benzene and 10 ml of dimethyl sulfoxide, 3.7 g (0.02 mol) of N-t-butyl-N-chloromethylcarbamoyl chloride and 4.6 g of 1,2-diphenylthiourea were dissolved. While stirring at room temperature, 6.1 g of 1,8-diazabicyclo [4,4,0] -7-undecene was added to the above solution, and stirring was further continued for 5 hours. The reaction mixture was poured into water and extracted with benzene.

The benzene layer was washed with water and dried. The crystals obtained by removing benzene from distillation were recrystallized from isopropyl alcohol. Yield 4.4g (65%), melting | fusing point 142-143 degreeC.

Example 6

2-isopropylimino-3-isopropyl-5-methyl-tetrahydro-1,3,5-thiadiazin-4-one (compound 1)

3.2 g (0.02 mol) of 1,3-diisoprourerea was added to 2.8 g (0.02 mol) of N-methyl-N-chloromethylcarbamoyl chloride dissolved in 50 ml of benzene. The mixture was stirred and heated at reflux for 2 hours. After cooling, 10 g of aqueous 30% potassium oxide and 50 ml of benzene were added to the mixture, and the mixture was shaken thoroughly. The separated layer was washed with water and dried, then benzene was distilled off under vacuum. The crystals thus obtained were ether recrystallized. Yield 3.0 g (66%), melting | fusing point 76-77 degreeC.

NMR (CDC1 ₂ ) δ: 1.15 (d.6H), 1.40 (d.6H), 3.10 (S.3H) 4.45 (S.2H) 4.50-4.80 (m.1H), 3.30-0 (m.1H) .

Example 7

-Ethylimino-3,5-diethyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 7)

In a mixture of 3.1 g (0.02 mol) of N-ethyl-N-chloromethylcarba mole chloride dissolved in 50 ml of benzene and 2.6 g (0.02 mol) of 1,3-edetylorea, 8 g of 20% sodium hydroxide solution was added at room temperature. Stir added. After stirring for 5 hours, the reaction mixture was poured into water and extracted with 50 ml of benzene. The benzene layer was washed with water, dried and benzene was distilled off under vacuum. The oily residue thus obtained was recrystallized from ether. Yield 2.8g (66%), Melting Point 68-70 ℃

NMR (CDC1 ₃ ) δ: 1.20 (t.9H), 3.20-3.70 (m.4H), 3.75-4.10 (q.2H), 4.40 (S.2H)

Example 8

2-isopropylimino-3-methyl-5-isopropyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 18)

In 50 ml of benzene, 3.4 g (0.02 mol) of N-isopropyl-N-chloromethylcarbamoyl chloride and 2.6 g (0.02 mol) of 1-isopropyl-3-methylthiourea were dissolved. This solution was heated at reflux for 2 hours. After cooling, the precipitated crystals (melting point, 198-200 ° C., decomposition) were collected by filtration, washed with a small amount of acetone, dissolved in 100 ml of water again, mixed with 10 ml of 30% potassium hydroxide solution, and extracted with 100 ml of benzene. . The benzene layer was washed with water, dried and distilled to remove benzene. The crystals thus obtained were recrystallized from ether. Quantity 3.8g (83%)

NMR (CDC1 ₃ ) δ: 1.10 (d6H), 1.16 (d.6H), 3.20 (S.3H), 4.33 (S. 2H), 4.40-4.85 (m. 1H), 3.30-3.70 (m.1H) .

Example 9

2-Methylimino-3-methyl-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4-silver (Compound No. 31)

In 50 ml of toluene, 3.7 g (0.02 mole) of N-t-butyl-N-chloromethylcaramoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea were dissolved. This solution was heated under reflux with stirring for hours. After cooling, the precipitated crystals (melting point> 220 DEG C decomposition) were collected by filtration, washed with a small amount of acetone, dissolved again in 100 ml of water, mixed with 10 ml of 20% sodium hydroxide solution, and extracted with 50 ml of benzene. The benzene layer was dried, concentrated under reduced pressure, and 3.5 g of crystals melted at 51 to 52 ° C. Yield 3.5g (83%).

NMR (CDC1 ₃ ) δ: 1.47 (s. 9H), 3.03 (s. 3H), 3.14 (s. 3H), 4.53 (s. 2H)

Example 10

2-t-butylimino-3-benzyl-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 47)

In 50 ml of xylten, 3.7 g (0.02 mol) of N-t-butyl-N-chloromethylcarba moyl chloride and 4.4 g (0.02 mol) of 1-t-butyl-3-benzylthiourea were dissolved. On the other hand, 8g of 30% potassium hydroxide solutions were added to this solution, stirring at room temperature. The mixture was stirred for another 4 hours while heating at 30 to 50 ° C. The reaction mixture was poured into water and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and the benzene was distilled off. The oily product thus obtained was crystallized with ether. Quantity 4.5g (68%), melting point 75-76 ℃

Example 11

2-Methylimino-3-methyl-5-benzyl-tetrahydro-1,3,5-thiadiazine-4-silver (Compound No. 54)

A mixture of 4.4 g (0.02 mol) of N-benzyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mol) of 1,3-dimethylthiourea was dissolved in 50 ml of ethyl alcohol, followed by stirring under reflux for 2 hours. Under heating. After adding 100 ml of potassium carbonate saturated solution, the mixture was extracted with 100 ml of benzene. The benzene layer was washed with water, dried and distilled off under reduced pressure to yield 4.0 g of crude crystals, which were recrystallized from ether. Yield 3.2g (63%), melting point 93-95 degreeC.

Example 12

2-t-butylimino-3-methyl-5- (1,1,3,3-tetramethyl) -butyl-tetrahydro-1,3,5-thiadiazin-4-one (Compound No. 63 )

In a mixture of 50 ml of benzene and 10 ml of dimethyl sulfoxide, 4.8 g (0.02 mol) of N- (1,1,3,3-tetramethyl) butyl-N-chloromethylcarbamoyl chloride and 1-3-t-methylbutyl 2.9 g (0.02 mol) of thiourea was dissolved. 2.8 g of powdered potassium carbonate was added to this solution under control, and stirring was further continued at 30 to 50 ° C for 4 hours. The reaction mixture was poured into water and extracted with 50 ml of benzene. The benzene layer was washed with water, dried and the benzene was distilled off under reduced pressure. The oily residue thus obtained was recrystallized from ether. Quantity 5.1g (82%), Melting point 91-93 degreeC

NMR (CDC1 ₃ ) δ: 0.97 (S. 9H). 1.20 (S. 9H), 1.50 (S. 6H), 1.90 (S. 2H), 3.18 (S. 3H), 4.54 (S. 2H), 4.54 (S. 2H).

Example 13

2-S-butylimino-3H-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 107)

8 g of 15% potassium hydroxide solution was added to a solution of S-butylthiourea 1.4 (0.01 mol) dissolved in 20 ml of acetone.

To the resulting mixture was added dropwise N-chloromethyl-N-t-butylcarbamoylchloride with stirring at room temperature.

After stirring for 30 minutes, the reaction mixture was poured into water and extracted with 100 ml of benzene. The benzene layer was dried and concentrated to give crude crystals, which were recrystallized from ether-isopropyl alcohol to give 1.6 g (63% yield) of crystals which solidified at 98 to 100 ° C.

Example 14

2-Imino-3H-5-t-butyl-tetrahydro-1,3,5-thiadiazine-4 (3H) -one (Compound No. 109)

To a suspension of 0.8 g (0.01 mol) of thiourea and 8 g of 15% potassium hydroxide solution in 50 ml of benzene was added 1.9 g (0.01 mol) of N-chloromethyl-N-t-butylcarbamoyl chloride while stirring at room temperature. After stirring for 1 hour at room temperature, the formed crystals were collected by filtration, and then recrystallized with chloroform to obtain 0.75 g (41% yield) of the crystal which solidified at 123 to 125 ° C.

Example 15

2-Methylimino-3-methyl-5-phenyl-tetrahydro-1,3,5-thiadiazine-4-silver (Compound No. 115)

2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.0 g (0.01 mol) of 1,3-dimethylthiourea were dissolved in 50 ml of benzene, and the resulting solution was heated under reflux while stirring for 3 hours. did. After cooling, the benzene layer was decanted from the reaction mixture and removed. The remaining layer was washed with a small amount of benzene. The residue (hydrogen chloride, melting point 168-170 占 폚, decomposition) was dissolved in water, mixed with 10 ml of 10% (W / W) aqueous sodium hydroxide solution, and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and benzene removed by distillation under reduced pressure to give crude crystals which were recrystallized from isopropyl alcohol. Yield 1.3g (51%), Melting point 68-70 degreeCδδ.

NMR (CDC1 ₃ ) δ: 3.15 (S. 3H), 3.30 (S. 3H), 4,80 (S. 2H), 7.33 (S. 5H)

Example 16

2-isopropylimino-3-methyl-5-phenyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 118)

In 50 ml of toluene, 2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.3 g (0.01 mol) of 1-isopropyl-3-methylthiourea were dissolved. To this solution was added 4 ml of 20% (W / W) aqueous sodium hydroxide solution at room temperature under stirring, and the mixture was stirred for 6 hours. The reaction mixture was decanted into water and extracted with 50 ml of benzene. The benzene layer was washed with water, dried and concentrated to give crude crystals which were recrystallized from isopropyl alcohol. Yield 1.3g (50%), Melting point 72-73.5 degreeC.

NMR (CDC1) δ: 1.15 (d. 6H), 3.29 (S. 3H), 3.25-3.85 (m. 1H), 4.73 (S. 2H), 7.28 (S. 5H)

Example 17

2-isopropylimino-3-isopropyl-5-phenyltetrahydro-1,3,5-thiadiazin-4-one (compound No. 144)

In 50 ml of benzene, 2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.6 g (0.01 mol) of 1,3-diisopropylthiourea were dissolved. The solution was heated at reflux with stirring for 2 hours. The crystals formed were collected by filtration, and the crystals (hydrogen chloride, melting point 188 to 190 DEG C) and decomposition were washed with a small amount of cold acetone, dissolved in water, mixed with 2.8 g of powdered sodium carbonate, and then extracted with 100 ml of benzene. did. The benzene layer was washed with water, dried and benzene was distilled off to give crude crystals which were recrystallized from isopropyl alcohol.

1.8g (62%), Melting Point 92 ~ 94 ℃

NMR spectrum (CDC1 ₃ ) δ: 1.15 (d. 6H), 1.49 (d. 6H), 3.25-3.68 (m. 1H), 4.82-4.99 * m. 1H), 4.75 S. 2H), 7.30 * S. 5H).

IR spectrum (KBr): vc =) 1660cm ^-1

Example 18

2-t-butylimino-3-isopropyl-5-phenyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 145).

In a mixture of 50 ml of acetone and 10 ml of dimethylformamide, 2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.7 g (0.01 mol) of 1-isopropyl-3-t-butylthiurea were dissolved. 4 ml of 30% (W / W) aqueous potassium hydroxide solution was added to the solution while stirring at room temperature, and the mixture was further stirred for 5 hours. The reaction mixture was poured into water and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated to give a viscous oil, which was crystallized from isopropyl alcohol. Yield 2.0 g (65%), melting point 104-106 degreeC.

NMR (CDC1 ₃ ) δ: 1.33 (S.9H), 1.45 (d. 6H), 4.70 (S. 2H), 4.32-5.00 (m. 1H), 67.30 (S. 5H)

Example 19

2-isopropylimino-3-isobutyl-5-phenyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 149).

In a mixture of 50 ml of tetrahydrofuran and 10 ml of dimethyl sulfoxide, 2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.7 g of 1-isopropyl-3-isobutylorea were dissolved. To this solution, on the other hand, 2.1 g of triethylamine was added while stirring at room temperature, and the mixture was further stirred for 6 hours. The reaction mixture was decanted into water and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated to give a viscous oil, which was crystallized from isopropyl alcohol. Yield 2.4g (78%), melting | fusing point 80-82 degreeC.

NMR (CDC1 ₃ ) δ: 0.90 (d. 6H), 1.15 (d. 6H), 1.70-2.30 (m. 1H), 3.35-3.75 (m. 1H), 4.05 (d. 2H), 4.75 (S. 2H), 7.30 (S. 5H)

Example 20

2-t-butylimino-3-cyclohexyl-5-phenyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 155)

2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride, 2.1 g (0.01 mol) of 1-cyclohexyl-3-t-butylthiourea and 1.6 g of pyridine were dissolved in 50 ml of ether. The resulting solution was stirred for 4 hours at room temperature. The reaction mixture was decanted into water and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated to give an oily residue, which was crystallized from isopropyl alcohol. Quantity 1.6g (45%), melting point 86-89 degreeC

NMR (CDC1 ₃ ) δ: 1.35 (S. 9H), 1.0-2.5 (m. 11H), 4.75 (S. 2H), 7.33 (S. 5H)

Example 21

2-benzylimino-3-methyl-5-phenyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 121)

1.8 g (0.01 mol) of 1-methyl-3-benzylthiourea was suspended in 20 ml of 6% (W / W) aqueous potassium hydroxide solution. 2.1 g of N-chloromethyl-N-phenylcarbamoyl chloride was added to the suspension with stirring at room temperature, and the mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was decanted into water and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated to give an oily residue which was then crystallized from isopropyl alcohol. The yield was 2.0 g (63%) and the melting point was 90 to 92 占 폚.

NMR (CDC1 ₃ ) δ: 3.35 (S. 3H), 4.50 (S. 2H), 4.65 (S. 2H), 7.0-7.5 (m. 10H).

Example 22

2-n-octylimino-3-methyl-5-phenyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 122):

1.5551Ethyl alcohol was passed through 2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 2.0 g (0.01 mol) of 1-methyl-3-n-octylthiourea. The solution was heated under reflux with stirring for 3 hours. After cooling, the reaction mixture was poured into water, mixed with 5 ml of 20% (W / W) aqueous sodium hydroxide solution and then extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated to give a viscous oily product, which was dissolved in 6N hydrochloric acid and the fluorine was extracted with benzene. 20% (W / W) sodium hydroxide aqueous solution was added to the aqueous layer, and it became weakly alkaline, and extracted with 50 ml of benzene. The benzene layer was washed with water, dried and concentrated to give an oily residue. Quantity 1.2 g (36%),

1.5551

Example 23

2-s-Butylimino-3,5-diphenyl-tetrahydro-1,3,5-thiadiazine-4-silver (compound No. 163):

2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.9 g (0.01 mo) of 1-s-butyl-3-phenylthiourea were dissolved in a mixture of 50 ml of ethyl acetate and 10 ml of dimethylformamide. I was. 1.1 g of powdered sodium carbonate was added to this solution, and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was poured into water and extracted with ethaneacetate. Ethyl acetate beans were washed with water, washed with water, dried and concentrated to give crude crystals, which were recrystallized from isopropyl alcohol. Yield 1.9g (57%), melting | fusing point 134-135.5 degreeC.

NMR (CDC1 ₃ ) δ: 0.5: 1.5 (m.8H), 3.0-3.5 (m. 1H), 4.85 (S. 2H), 7.25 (S. 10H)

Example 24

2- (2-methyl) phenylimino-3-methyl-5-phenyltetrahydro-1,3,5-thiadiazin-4-one (compound No. 124)

2.1 g (0.01 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1.8 g (0.01 mol) of 1-methyl-3-0-rollylthiourea were dissolved in 50 ml of benzene. To this solution, on the other hand, 3.1 g of 1,8-diazabicyclo- [5,4,0] -7-undecene was added with stirring at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was poured into water and extracted with 100 ml of benzene. The benzene layer was washed with water, dried and concentrated to give crude crystals which were recrystallized from isopropyl alcohol. Yield 2.0 g (63%), viscous 113-114 degreeC.

NMR (CDC1 ₃ ) δ: 2.18 (S. 3H), 3.50 (S. 3H), 4.68 (S. 2H), 7.075 (m.9H).

Example 25

2-Methylimino-3- (2-methyl-4-chloro) -phenyl-5-phenyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 166):

In a mixture of 10 ml of benzene and 10 ml of tetrahydrofuran 1.4 g (1/150 mol) of N-chloromethyl-N-phenylcarbamoyl chloride and 1-methyl-3- (2-methyl-4-chloro) -phenylthiourea 1.4 g (1/150 mole) was dissolved. To the solution was added stirring 5.5 g of an aqueous 10% (W / W) sodium hydroxide solution, and the mixture was reacted vigorously for 4 hours while maintaining the reaction temperature at 40 ° C on the one hand. After completion of the reaction, the benzene layer was washed with water and concentrated to 2-methylimino-3- (2-methyl-4-chloro) -phenyl-5-phenyl-tetrahydro-1.3.5-thiadiazine-4- 2- (2-ethyl-4-chloro) phenylimino-3-methyl-5- oily mixture of on and -tetrahydro-1,3,5-thiadiazin-4-one was obtained.

Compound No. 166 can be separated from the mixture in the following manner.

The oily mixture was dissolved in 3N hydrochloric acid, and the insoluble matter was removed by washing with ethyl acetate. The aqueous layer was weakly alkaline to precipitate, and this was recrystallized from isopropyl alcohol-n-hexane to obtain 1.2 g (52% yield) of compound No. 166 which was melted at 121-123 ° C.

NMR (CDC1 ₃ ) δ: 2.18 (S. 3H), 3.07 (S. 3H: = N-CH ₃ ), 4.92 (S. 2H).

Example 26

2-Methylimino-3-methyl-5-(-P-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 188)

2.4 g of N-chloromethyl-N- (P-chlorophenyl) -carbamoyl chloride and 1.0 g (0.01 mol) of 1,3-dimethylthiourea were dissolved in 50 ml of benzene. This solution was heated at reflux for 1 hour. The crystals formed were collected by filtration and washed with acetone. The resulting white crystals (hydrogen chloride, melting point 205 DEG C) were dissolved in water, mixed with 5 ml of 20% sodium hydroxide solution, thoroughly stirred and extracted with benzene. Crystals obtained by removing benzene by distillation were recrystallized with isopropyl alcohol to obtain 1.6 g (60% yield) of crystals melted at 98 to 100 ° C.

Example 27

2-Isopropylimino-3-methyl-5-(-P-chlorophenyl) -tetrahydro-1,3,4-thiadiazin-4-one (compound No. 189):

2.4 g (0.01 mol) of benzene 50 ml N-chlorophenyl-N- (P-chlorophenyl) -carbamoyl chloride and 1.3 g (0.01 mol) of 1-isopropyl-3-methylthiourea were dissolved and dissolved in this solution. 8 ml of 10% sodium hydroxide solution was added dropwise with stirring, and the mixture was further stirred at 40 ° C. for 4 hours. The reaction mixture was decanted into water and extracted with benzene. The benzene layer was washed with water, dried and benzene removed by distillation to give crystals which were recrystallized from isopropyl alcohol. 2.4 g (82% yield) of crystals melted at 106 to 108 ° C were obtained.

NMR (CDC1 ₃ ) δ: 1.18 (d. 6H), 3.32 (S. 3H), 3.55 (m. 1H), 4.80 (S. 2H), 7.25 (S. 4H)

In a similar manner to that described above, 2.3 g (0.01 mol) of 1-isopropyl-3-t-octylthiourea and 2.7 g (0.01 mol) of N-chloromethyl-Nm-trifluoromethylphenylcarbamoyl chloride were treated. 2-t-octylimino-3-isopropyl-5- (m-trifluoromethylphenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 266) was obtained as an oil. Obtained.

1.5089 NMR (CDC1 ₃ ) δ: 4.70 (S. 2H-NCH ₂ -S-)

Example 28

2-t-butylimino-3-isopropyl-5-(-P-chlorophenyl) -tetrahydro-1,3,4-thiadiazin-4-one (compound No. 196):

In 50 ml of benzene, 2.4 g (0.01 mol) of N-chloromethyl-N- (P-chlorophenyl) -carbamoyl chloride and 1.7 g (0.01 mol) of 1-isopropyl-3-t-butylthiourea were dissolved. After addition of 8 ml of 15% potassium hydroxide solution, the mixture was heated at 40-50 ° C. and stirred for 4 hours with stirring. The reaction mixture was poured into water and extracted with benzene. The benzene layer was washed with water, dried and benzene was distilled off to give crude crystals which were recrystallized from ethanol. Yield 2.0 g (62%) of crystals melting at 123 to 125 DEG C was obtained.

Example 29

2-t-butylimino-3-benzyl-5-(-P-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 204):

In 50 ml of toluene, 2.4 g (0.01 mol) of N-chloromethyl-N- (P-chlorophenyl) -carbamoyl chloride and 2.2 g (0.01 mol) of 1-t-butyl-3-benzylthiourea were dissolved. After adding 8 ml of 10% sodium hydroxide solution, the mixture was stirred for 4 hours and heated at 40 to 50 ° C. The reaction mixture was washed with water, the toluene layer was dried and the toluene was removed by distillation to give crude crystals which were recrystallized from isopropyl alcohol. 2.8 g (73% yield) of crystals melted at 87 to 89 ° C were obtained.

Example 30

2-t-butylimino-3-ethyl-5- (m-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 216):

In 50 ml of tetrahydrofuran, 2.4 g (0.01 mol) of N-chloromethyl-N- (m-chlorophenyl) -carbamoyl chloride and 1.6 g (0.01 mol) of 1-ethyl-3-t-butylthiourea were dissolved. . After addition of 8 ml of 15% potassium hydroxide solution, the mixture was heated at 40-50 ° C. with stirring for 4 hours. The reaction mixture was poured into water and extracted with benzene. The benzene layer was dried and concentrated to give a viscous oil.

Example 31

2-t-butylimino-3-s-butyl-5- (m-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 225):

In 50 ml of xylene, 2.4 g (0.01 mol) of N-chloromethyl (m-chlorophenyl) -carbamoyl chloride and 1.8 g (0.01 mol) of 1-s-butyl-3-t-butylthiourea were dissolved. After addition of 8 ml of 10% sodium hydroxide solution, the mixture was heated at 40-50 ° C. with stirring for 4 hours. The reaction mixture was washed with water, dried and dried hydrogen chloride gas was introduced into the xylene solution at room temperature until no more crystals were precipitated. The crystals were collected by filtration and washed with acetone. Crystals (hydrogen chloride, melting point 186 DEG C. decomposition) were suspended in water, mixed with 10 ml of 15% potassium hydroxide solution, stirred well and extracted with benzene. The benzene layer was dried, and benzene was removed by distillation to obtain 1.9 g (60% yield) of white crystals melted at 75 to 76 ° C.

Example 32

2-Isopropylimino-isopropyl-5- (0-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 244):

In 50 ml of benzene, 2.4 g (0.01 mol) of N-chloromethyl-N- (0-chlorophenyl) -carbamoyl chloride and 1.6 g (0.01 mol) of 1,3-diisopropyl thiourea were dissolved. After adding 8 ml of 10% sodium hydroxide solution, the mixture was heated at 50 to 60 ° C while stirring for 4 hours. The reaction mixture was washed with water, dried and benzene removed by distillation to give crude crystals which were recrystallized from isopropyl alcohol to give 1.8 g (56% yield) of crystals which melted at 95-96 ° C.

NMR (CDC1 ₃ ) δ: 1.15 (d. 6H), 1.45 (d. 6H), 4.68 (S. 2H), 3.50 (m. 1H), 4.73 (m. 1H), 7.15 (m. 4H)

This method was followed by using 1.7 g (0.01 mol) of 1-isopropyl-3-t-butylthiourea in 2-t-butylimino-3-isopropyl-5- (o-chlorophenyl) -tetrahydro- 1,3,5-thiadiazin-4-one (white crystals of compound No. 245 (melting point: 88-89 ° C.) was obtained.) Yield 2.3 g (70%)

This crystal was dissolved in benzene and hydrogen chloride gas was introduced into the solution. The precipitated crystals were collected by filtration, washed with acetone to obtain crystalline hydrogen chloride (decomposition) that melted at 210 ° C.

In a similar manner, 1.7 g (0.01 mol) of 1-isopropyl-3-S-butylthiourea and 2.2 g (0.01 mol) of N-chloromethyl-N- (P-fluorophenyl) -carbamoyl chloride were added. It reacted and produced | generated the crystal | melting which melt | dissolves at 81-82 degreeC. The crystal showed a single point in the thin layer chromatogram using hexane-acetone mixture (8: 2) as the developing solvent. However, the NMR spectrum indicated that the crystals were mixed at approximately 1: 1 with compound 361 and compound 362 as follows:

2-Isopropylimino-3-S-butyl-5- (P-fluorotomatic) -tetrahydro-1.3.5-thiadiazin-4-one:

2-S-butylimino-3-isopropyl-5- (P-fluorophenyl) -tetrahydro-1.3.5-thiadiazin-4-one:

Example 33

2-Methylimino-3-methyl-5- (P-fluorophenyl) -tetrahydro-1,3,5-thiadiazine-4- is a hydrochloride (Compound No. 277):

1.0 g (0.01 mol) of 1,3-dimethylthiourea and 2.2 g (0.01 mol) of N-chloromethyl-N- (P-fluorophenyl) -carbamoyl chloride were dissolved in 50 ml of benzene. The solution was heated under reflux with stirring for 1 hour. The oily product obtained by removing benzene by distillation was dissolved in acetone, and the precipitated crystals were collected by filtration and washed with acetone to obtain 2.1 g (85% yield) of white crystals of hydrogen chloride water which melted at 221 DEG C (decomposition). A portion (1 g) of crystals was dissolved in 20 ml of water, mixed with 5 ml of 10% sodium hydroxide solution, stirred thoroughly and extracted with benzene. The benzene layer was dried, concentrated to give crystals of free base which melted at 105 to 106 캜.

In a similar manner, 1.7 g (0.01 mol) of 1-isopropyl-3-t-butylthiourea was mixed with 2.2 g (0.1 mol) of N-chloromethyl-N- (P-fluorophenyl) -carbamoyl chloride. The reaction was carried out to prepare 2-t-butylimino-3-isopropyl-5- (P-fluorophenyl) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 282) as follows. Obtained in the form of hydrogen chloride, melting at ˜190 ° C.

The crystals were suspended in 20 ml of water and treated in a similar manner as described above to give white crystals of free base which melt at 109-110 ° C. (decomposition) (isopropanol). Yield 2.0 g (63%).

Example 34

2-Isopropylimino-3-allyl-5- (m-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 217):

을 80%의 수율로 수득했다.In 50 ml of benzene, 2.4 g (0.01 mol) of N-chloromethyl-N- (m-chlorophenyl) -carbamoyl chloride and 1.58 g (0.01 mol) of 1-allyl-3-isopropylthiourea were dissolved. After adding 8 ml of 10% sodium hydroxide solution to the solution, the mixture was stirred at 4-50 ° C. while stirring for 4 hours. The reaction mixture was washed with water, dried and concentrated to give an oily residue.

Was obtained in 80% yield.

The oily residue was dissolved in benzene, and hydrogen chloride gas was introduced into this solution to obtain a hydrogen chloride melted at 179 ° C (decomposition).

Example 35

2-t-butylimino-3-isopropyl-5- (m-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 211):

In 50 ml of benzene, 2.4 g (0.01 mol) of N-chloromethyl-N- (m-chlorophenyl) -carbamoyl chloride and 1.74 g (0.01 mol) of 1-isopropyl-3-t-butylthiourea were dissolved. After addition of 8 ml of 10% sodium hydroxide solution, the mixture was heated at 40-50 ° C. with stirring for 4 hours. The benzene layer was washed with water, dried and concentrated to give a viscous oily product which was crystallized with isopropyl alcohol to obtain 1.5 g (45 yield) of white crystals melting at 113 to 115 占 폚. This crystal was dissolved in benzene, and hydrogen chloride gas was passed through to obtain hydrogen chloride which melted at 152 占 폚 (decomposition).

Example 36

2-cyclohexylimino-3-isopropyl-5- (0-chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 252):

2.4 g (0.01 mol) of N-chloromethyl-N- (0-chlorophenyl) -carbamoyl chloride and 2.0 g (0.01 mol) of 1-isopropyl-3-cyclohexylthiourea were dissolved in 50 ml benzene. After addition of 8 ml of 10% sodium hydroxide solution, the mixture was heated at 40-50 ° C. with stirring for 4 hours. After completion of the reaction, the benzene layer was washed with water, dried and concentrated to give a viscous oily product, which was crystallized with isopropyl alcohol-n-hexane (1: 1) to melt 22.5% of white crystals at 123 to 125 ° C. Gained in yield.

Example 37

2-ethylimino-3-phenyl-5-(-0chlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 256):

2.4 g (0.01 mol) of N-chloromethyl-N- (0-chlorophenyl) -carbamoyl chloride and 1.8 g (0.01 mol) of 1-ethyl-3-phenylthiourea were dissolved in 50 ml benzene. After addition of 8 ml of 10% sodium hydroxide solution, the mixture was heated at 40-50 ° C. while stirring for 4 hours. After completion of the reaction, the benzene layer was washed with water, dried and concentrated to give a viscous oily product, which was crystallized with isopropyl alcohol-n-hexane (1: 1) and melted at 77-79 ° C. 0.8 g ( 14% yield).

Example 38

2-Isopropylimino-3-isopropyl-5- (m-trifluoromethylphenyl-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 265):

In 50 ml benzene, 2.7 g (0.01 mol) of N-chloromethyl-N- (m-trifluoromethylphenyl) -carbamoyl chloride and 1. g (0.01 mol) of 1,3-diisopropylthiourea were dissolved. After addition of 8 ml of 10% sodium hydroxide solution, the mixture was heated at 40-50 ° C. while stirring for 4 hours. After completion of the reaction, the benzene layer was washed with water, dried and concentrated to give a viscous oily product, which was crystallized with isopropyl alcohol-n-hexane (1: 1) and 1.3 g of white crystals melted at 67 to 68 ° C. (36% yield).

Example 39

2-t-butylimino-3-isopropyl-5- (P-tolyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 318):

1.0 g (0.0028 mol) of 1,3,5-tris (P-tolyl) -hexahydro-s-triazine was suspended in 10 ml of tetrahydrofuran. The resulting suspension was added dropwise to 5 ml of ice cold benzene containing 0.9 g (0.0042 mol) of trichloromethylchloroformate under stirring. After completion of the dropwise reaction, the mixture was stirred at room temperature for 1 hour. To this mixture was added 20 ml of benzene containing 1.4 g (0.0083 mol) of 1-isopropyl-3-t-butylthiourea. After addition of 7 ml of 10% sodium hydroxide solution, the mixture was stirred at 40-50 ° C. for 4-6 hours. The reaction mixture was washed with water, dried and benzene removed by distillation. The crude product thus obtained was recrystallized from isopropyl alcohol to obtain 1.2 g (45% yield) of white crystals melting at 118 to 120 ° C.

NMR (CDC1 ₃ ) δ: 4.75 (s. 2H), 4.70 (m. 1H), 2.35 (s. 3H), 1.47 (d. 6H), 1.33 (s. 9H)

Example 40

2-benzylimino-3-benzyl-5- (p-tolyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 321):

1.0 g (0.0028 mol) of 1,3,5-tris (p-tolyl) -hexahydro-s-triazine was suspended in 10 ml of tetrahydrofuran. This suspension was added dropwise to 5 ml of benzene containing 0.9 g (0.0042) of trichloromethylchloroformate while stirring at room temperature. Thereafter, the mixture was stirred at room temperature for 1 hour. To this mixture was added 21 g (0.0083 mol) of 1,3-bis (benzyl) thiourea dissolved in 20 ml of benzene, followed by 7 ml of 10% sodium hydroxide solution. The mixture was stirred at rt for 7 h. The mixture was stirred at rt for 7 h. The mixture was stirred for 7 hours at room temperature. The reaction mixture was washed with water, dried and distilled off to remove benzene to give crude crystals which were recrystallized from isopropyl alcohol to yield 1.7 g (51% yield) of white crystals melting at 152-153 ° C. .

) 4.78(s. 2H), 4.50(s 2H, =N-CH₂-), 2.32(s. 3H).NM (CDC1 ₃ ) δ: 7.2 (m. 14H), 5.32 (s. 2H,

) 4.78 (s. 2H), 4.50 (s 2H, = N-CH _2- ), 2.32 (s. 3H).

Example 41

2-isopropylimino-3-isopropyl-5- (0-tolyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 301).

.A solution of 2.4 g (0.0067 mol) of 1,3,5-tris (0-tolyl) -hexahydro-s-triazine dissolved in 10 ml of tetrahydrofuran was stirred at room temperature while 2.0 g of trifluoromethylchloroformate ( 0.01 mole) was added dropwise to 10 ml of benzene. Thereafter, the mixture was stirred at 30 ° C. for 30 minutes. To this mixture was added a solution of 3.2 g (0.02 mol) of 1,3-diisopropylthiourea dissolved in 30 ml of benzene, followed by 16 ml of 10% sodium hydroxide solution. The mixture was stirred at 40 ° C. for 4 hours, washed with water, dried and benzene removed by distillation. The oily residue was mixed with n-hexane and filtered to remove insoluble matter. n-hexane was separated from the filtrate by distillation to give 3 g (40%) yield of colorless oil.

.

) 4.52(s. 2H), 3.48(m. 1H, =N-CH₁), 22.3(s. 3H), 14.9(b. 6H), 1.17(d. 6H).NMR (CDC1 ₃ ) δ: 4.77 (m-1H,

) 4.52 (s. 2H), 3.48 (m. 1H, = N-CH ₁ ), 22.3 (s. 3H), 14.9 (b. 6H), 1.17 (d. 6H).

1.5 g (0.0042 mol) of 1,3,5-tris (0-tolyl) -hexahydro-s-triazine followed by 1.3 g (0.0063 mol) of trichloromethylchloroformate, 1,3-bis 2-cyclohexylimino-3-cyclohexyl-5- (o-tolyl) -tetra having the following structure using 3.0 g (0.013 mole) of (cyclohexyl) -thiourea and 11 ml of 10% sodium hydroxide solution Hydro-1.3.5-thiadiazin-4-one (compound No. 307) was obtained as a colorless oil.

In a similar manner, 1.7 g (0.004 mole) of hexahydro-1,3,5-tris (p-ethylphenyl) -s-triazine, 1.3 g (0.006 mole) of trichloromethylchloroformate, 1,3- 2-methylimino-3-methyl-5- (p-ethylphenyl) -tetrahydro-1,3 having the following structure using 1.3 g (0.02 mol) of dimethylthiourea and 11 ml of 10% sodium hydroxide solution. 0.8 g (24% yield) of, 5-thiadiazin-4-one (compound No. 331) was obtained as a colorless oil.

Similarly, 1.7 g (0.004 mole) hexahydro-1,3,5-tris (p-ethylphenyl) -s-triazine, 1.3 g (0.006 mole) trichloromethylchloroformate, 1-isopropyl-3 2-t-butylimino-3-isopropyl-5- (P-fluorophenyl) -tetra of the following formula using 2.2 g (0.012 mol) of butylthiourea and 11 ml of 10% sodium hydroxide solution Hydro-1.3.5-thiadiazin-4-one (compound No. 133) was obtained as white crystals (melting point 70-72 ° C.)

Similarly, 2.2 g (0.006 mol) of hexahydro-1,3,5-tris (0-ethylphenyl) -s-triazine, 1.7 g (0.008 mol) of trichloromethylchloroformate, 1-s-butyl- 2-t-butylimino-3-s-butyl-5- (0-ethylphenyl) having the following structure using 3.1 g (0.0016 mol) of 3-t-butylthiourea and 15 ml of 10% sodium hydroxide solution ) -Tetrahydro-1.3.5-thiadiazin-4-one (compound No. 339) was obtained as a colorless viscous oil. .

Example 42

2-t-butylimino-3-isopropyl-5- (p-methoxyphenyl) -tetrahydro-1,3,4-thiadiazin-4-one (353 compound):

2.7 g (0.0067 mol) of 1,3,5-tris (p-methoxyphenyl) -hexahydro-s-triazine was suspended in 20 ml of tetrahydrofuran. The suspension was added dropwise to 10 ml of benzene containing 2.0 g (0.01 mol) of trichloromethylchloroformate while stirring at room temperature and further stirred at 30 ° C. for 30 minutes. To this mixture was added to a solution of 3.5 g (0.02 mol) of 1-isopropyl-3-t-butylthiourea dissolved in 30 ml of benzene. Then 16 ml of 10% sodium hydroxide solution was added. The mixture was stirred at 40 ° C. for 4 hours, washed with water, dried and benzene removed by distillation. The residual oil was mixed with n-hexane and filtered to remove insolubles. The filtrate was removed from n-hexane by distillation to give 3.4 g (51% yield) of white crystals which melted at 99-101.5 占 폚.

NMR (CDC1 ₃ ) δ: 4.64 (s.2H), 4.59 (m. 1H), 3.75 (s. 3H), 1.43 (d. 6H), 1.31 (s. 9H)

Similarly, 2.7 g (0.0067 mol) of 1,3,5-tris (p-methoxyphenyl) -hexahydro-s-triazine, 2.0 g (0.01 mol) of trichloromethylchloroformate, 1-s-butyl 2-t-butylimino-3-s-butyl-5- (P-methoxy) having the following structure using 3.8 g (0.02 mol) of 3-t-butylthiourea and 16 ml of 10% sodium hydroxide solution Phenol) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 355) was obtained by melting white crystals at 63 占 폚.

NMR (CDC13) δ: 4.70 (s. 2H), 4.36 (q. 1H), 3.75 (s. 3H), 1.9 (m. 2H), 1.47 (d. 3H), 1.32 (s. 9H), 0.92 ( t. 3H)

Similarly, 1.4 g (0.0033 mol) of 1,3,5-tris (p-methoxyphenyl) -hexahydro-s-triazine, 1 g (0.005 mol) of trichloromethylchloroformate, 1-isophorophil- 2-isopropylimino-3-benzyl-5- (P-methoxyphenyl) -tetrahydro- of the following formula using 2.1 g (0.01 mol) of 3-benzylthiourea and 9 ml of 10% sodium hydroxide solution 1.9 g (52% yield) of 1.3.5-thiadiazin-4-one (compound No. 356) were obtained as white crystals which melted at 114 ° C.

)4.72(s. 2H), 3.75(s. 3H), 3.52(m. 1H), 1.09(d. 6H)NMR (CDC13): 5.29 (s. 2H,

) 4.72 (s. 2H), 3.75 (s. 3H), 3.52 (m. 1H), 1.09 (d. 6H)

Example 43

2-t-butylimino-3-isopropyl-5- (0-isopropyl) -phenyl-tetrahydro-1,3,4-thiadiazin-4-one (compound 343):

1.0 g of trichloromethylchloroformate while stirring at room temperature in a solution of 1.4 g (0.003 mol) of 1,3,5-tris (0-isopropyl) phenyl-hexahydro-s-triazine dissolved in 20 ml of tetrahydrofuran. I dropped it. After 10 minutes of stirring, a solution of 1.7 g of 1-isopropyl-3-t-butylthiourea dissolved in 20 ml of benzene was added to the mixture, followed by 8 ml of 15% potassium hydroxide solution. The mixture was stirred at 40-50 ° C. for 3 hours. The reaction mixture was poured into water and extracted with 50 ml of benzene. The benzene layer was dried, the benzene was removed by distillation to give crude crystals, which were recrystallized from isopropyl alcohol to obtain 1.7 g (52% yield) of white crystals melting at 108-109 ° C.

Example 44

2-Isopropylimino-3-isopropyl-5- (p-bromophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 293):

In 50 ml of benzene, 2.8 g (0.01 mol) of N-chloromethyl-N- (p-bromophenyl) -carbamoyl chloride and 1.6 g of 1,3-diisopropylthiourea were dissolved. To this solution was added 4 ml of 20% sodium hydroxide solution with stirring, and the mixture was fielded at 40-50 ° C. for 4 hours. The reaction mixture was washed with water, dried and distilled off to remove benzene to give crude crystals which were recrystallized from isopropyl alcohol to give 1.6 g (45% yield) of white crystals melting at 121-122 ° C.

Example 45

2-t-butylimino-5-s-butyl-5- (4-ethoxyphenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 368):

A solution of 1.50 g (0.0033 mol) of hexahydro-1,3,5-tris (4-ethoxyphenyl) -s-triazine dissolved in 10 ml of tetrahydrofuran was stirred with 10 ml of benzene containing 1.1 g of phosgene while stirring While dropping. To this mixture was added 1.88 g of 1-s-butyl-3-t-butylthiourea followed by 15% potassium hydroxide solution. The mixture was stirred at 40-50 ° C. for 4 hours. The reaction mixture was poured into water and extracted with 50 ml of benzene. The benzene layer was washed with water, dried and then concentrated. The crude crystal thus formed was recrystallized from isopropyl alcohol to obtain 1.7 g (46% yield) of white crystals melted at 66-67 ° C.

Example 46

2-ethylimino-3-ethyl-5- (3,4-dichlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 413):

2.73 g (0.001 mol) of N- (3,4-dichlorophenyl) -N-chloromethylcarbamoyl chloride and 1.32 g (0.01 mo) of 1,3-diethylthiourea were added to a conical pull flask, and a uniform solution was added. Made. 8 ml of 10% sodium hydroxide solution was added to the solution, and the reaction solution was reacted by stirring for 4 hours in a water bath between 40-50 ° C. After the reaction was completed, the benzene layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The oily residue was recrystallized from isopropyl alcohol to obtain 1.4 g (43% yield) of white crystals melting at 86-88 ° C.

Example 47

2-Benzylimino-3-benzyl-5- (3,4-dichlorophenyl) -tetrahydro-1, 3,5-thiadiazin-4-one (compound No. 423):

2.73 g (0.01 mol) of N- (3,4-dichlorophenyl) -N-chloromethylcarbamoyl chloride and 2.56 g (0.01 mol) of 1,3-dibenzylthiourea were added to the reactor. Tetrahydrofuran was added to this mixture to make a uniform solution. To this solution was added 8 ml of a 10% sodium hydroxide solution and the reaction mixture was reacted with stirring in a 40-50 ° C. water bath. After the reaction was completed, the benzene layer was washed with water, dried over anhydrous sodium sulfate, and hydrogen chloride gas was introduced into the benzene layer to obtain a hydrogen chloride product of the target compound. Hydrogen chloride was added to a mixture of 10 ml of 10% aqueous 10% sodium hydroxide solution and 10 ml of benzene to obtain 1.5 g (33% yield) of white crystals of the target compound as a free base that melted at 118-120 ° C.

Example 48

2-t-butylimino-3-isopropyl-5- (3,4-dichlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 416):

In the reactor, 2.73 g (0.01 mol) of N- (3,4-dichlorophenyl) -N-chloromethylcarbamoylchloride, 30 ml of benzene and 1.74 g (0.01 mol) of 1-ispropyl-3-t-butylthiourea Put it. 8 ml of 10% sodium hydroxide solution was added dropwise to the reaction mixture. The reaction mixture was reacted with stirring for 4 hours in a 40-50 ° C. water bath. The reaction mixture was treated in a similar manner to that described in Example 46 to obtain 0.9 g of molten white crystals at 114.5-117.5 ° C.

Example 49

2-Isopropylimino-3-benzyl-5- (3,5-dichlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 408):

In the reactor, 1.37 g (0.005 mol) of N- (3,5-dichlorophenyl) -N-chloromethylcarbamoyl chloride, 1.04 g (0.005 mol) of 1-benzyl-3-isopropylthiourea and 20 ml of benzene were added. . After 4 ml of 10% aqueous sodium hydroxide solution was added dropwise, the reaction mixture was reacted for 2 hours in a 40-50 ° C. water bath. After the reaction was completed, the benzene layer was washed with water, dried, and hydrogen chloride gas was passed through the benzene layer to obtain a hydrogen chloride product of the target compound. This hydrogen chloride was added to a mixture of 10 ml of 10% aqueous sodium hydroxide solution and 20 ml of benzene to dissolve the free free base in benzene. The benzene layer was concentrated, and the oily product obtained as a residue was crystallized with a mixture of isopropyl alcohol-n-hexane (1: 1 V / V) to obtain 0.8 g (39% yield) of white crystals melting at 90-92 ° C. .

Example 50

2-Isopropylimino-3-aryl-5- (3,5-dichlorophenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 412):

1.5962 0.8g(22.3% 수율)을 얻었다.In the reactor, 2.73 g (0.01 mo) of N- (3,5-dichlorophenyl) -N-chloromethylcarbamoyl chloride, 1.58 g of 1-allyl-3-isopropylthiourea and 30 ml of benzene were charged. 8 ml of 10% aqueous sodium hydroxide solution was added dropwise to the mixture, and the resulting mixture was reacted with stirring for 4 hours in a water bath at 40-50 ° C. After completion of the reaction, the layer was washed with water, dried and concentrated to give an oil as a residue. The oily substance was purified by silica gel column chromatography to obtain oil (

1.5962 0.8 g (22.3% yield) was obtained.

Example 51

2-t-butylimino-s-butyl-5- (p-ethoxyphenyl) -tetrahydro-1,3,5-thiadiazin-4-one (mixture 368):

A solution of 1,3,5-tris- (p-ethoxyphenyl) -hexahydro-s-triazine g (0.006 mol) dissolved in 10 ml of tetrahydrofuran was stirred at room temperature with trichloromethylchromophoromate 1.8 It was added dropwise to 10 ml containing g (0.009 mol), and the mixture was further stirred at 40 ° C for 20 minutes. To this mixture was added a suspension of 3.1 g (0.017 mol) of s-butyl-3-t-butylthiourea suspended in 20 ml of benzene, followed by 15 g of 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at 40 ° C. for 3 hours, then the reaction mixture was washed with water, dried and distilled to remove benzene. The oily residue was mixed with n-hexane and filtered to remove insolubles. The filtrate was distilled off to remove n-hexane, to obtain crude crystals which were recrystallized from isopropyl alcohol to give 3.2 g (53% yield) of white crystals melting at 66-67 ° C.

In a similar manner, 2.4 g (0.00 mol) of 1,3,5-tris (2,3-dimethylphenyl) -hexahydro-s-triazine, 1.8 g (0.009 mol) of trichloromethylchloroformate, 1- 2-cyclohexylimino-3-ethyl-5- (2,3-tylphenyl) having the following structural formula using 3.1 g (0.07 mol) of ethyl 3-cyclohexyl-thiourea and 15% of 10% aqueous sodium oxide solution 3.5 g (61% yield) of) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 382) were obtained as crystals melting at 151-152 ° C.

Similarly, 2.4 g (0.006 mol) of 1,3,5-tris- (2,3-dimethylphenyl) -hexahydro-s-triazine, 1.8 g (0.009 mol) of trichloromethylchloroformate, 1- Using 2.9 g (0.017 mole) of isopropyl-3-t-butylthiourea and 15 g of 10% aqueous sodium hydroxide solution, the following structural formula was used. The white crystal 2-t-butylimino melted at 91-92 ° C. -3-isopropyl-5- (2,3-dimethylphenyl) -1.3.5-thiadiazin-4-one (compound No. 384) was obtained.

인 2-t-부틸이미노-3-벤질-5-(2,3-디메틸페닐)-테트라하이드로-1,3,5-티아디아진-4-온(제386번 화합물)을 얻었다.Similarly, 1.6 g (0.0004 mol) of 13,5-tris (2,3-dimethylphenyl) -hexahydro-s-triazine, 1.2 g (0.006 mol) of trichloromethylchloroformate, 1-benzyl-3 Colorless oily product having the following structural formula using 2.7 g (0.012 mol) of -t-butylthiourea and 11 g of 10% aqueous sodium hydroxide solution.

Phosphorus 2-t-butylimino-3-benzyl-5- (2,3-dimethylphenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 386) was obtained.

Example 52

2-Isopropylimino-3-methyl-5- (p-isopropoxyphenyl) -tetrahydro-1,3,4-thiadiazin-4-one (compound No. 370):

A solution of 2.8 g (0.00 mol) of 1,3,5-tris- (p-isopropoxyphenyl) -hexahydro-s-triazine dissolved in 10 ml of tetrahydrofuran was 1.8 g of trichloromethylchloroformate at room temperature. (0.009 mol) was added dropwise to 10 ml of benzene and the mixture was stirred at 40 ° C. for 20 minutes. To the reaction mixture was added a suspension of 2.2 g (0.017 mol) of 1-methyl-3-isopropylthiourea dissolved in 20 ml of benzene, followed by 15 g of 10% aqueous sodium hydroxide solution for at least about 1 hour. Thereafter, the mixture was stirred for 2 hours at 50 ° C. The reaction mixture was washed with water and the remaining benzene layer was mixed with 20 ml of 3N hydrochloric acid to form hydrogen chloride of the desired compound. The aqueous layer containing hydrogen chloride was washed again with fresh benzene, made sufficiently alkaline with alkaline solution and then extracted with benzene. The benzene layer was washed with water, dried and distilled to remove benzene. The residue was recrystallized from isopropyl alcohol and 1.2 g (23% yield) of white crystals melted at 112-113 ° C.

In a similar manner, 1,3,5-tris (p-isopropoxyphenyl) -hexahydro-s-triazine 2.8 g (0.006 mol), trichloromethylchloroformate 1.8 g (0.009 mol), 1, Using 2.6 g (0.016 mole) of 3-diisopropylthiourea and 15 g of 10% aqueous sodium hydroxide solution, the following structural formula is used. 2-t-butylimino-3- as white crystal melting at 60-61 ° C. 1.4 g (24% yield) of isopropyl-5- (P-isopropoxyphenyl) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 372) were obtained.

로서 2-t-부틸이미노-3-이소프로필-5-(2-메틸-4-클로로페닐)-테트라하이드로-1.3.5-티아디아진-4-온(제 387번 화합물) 1.5g(25% 수율)을 얻었다.Similarly, 1,3,5-tris (p-isopropoxyphenyl) -hexahydro-s-triazine 2.8 g (0.006 mol), trichloromethylchloroformate 1.8 g (0.009 mol), 1- Colorless oily product having the following structural formula using 3.0 g (0.016 mol) of s-butyl-3-t-butylthiourea and 15 g of 10% aqueous sodium hydroxide solution.

1.5 g of 2-t-butylimino-3-isopropyl-5- (2-methyl-4-chlorophenyl) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 387) as 25% yield).

Similarly, 2.0 g (0.0904 mol) of 1,3,5-tris (p-isopropoxyphenyl) -hexahydro-s-triazine, 1.2 g (0.006 mol) of trichloromethylchloroformate, 1,3 Dibenzylthiourea 3.1 g (0.012 mol) and 10 g sodium hydroxide aqueous solution 11 g having the following structural formula, 2-benzylimino-3-benzyl-5- as white crystals melting at 141-142 ℃ 1.5 g (28% yield) of (P-isopropoxyphenyl) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 375) were obtained.

Example 53

2-Isopropylimino-3-methyl-5- (2,4-dimethylphenyl) -tetrahydro-1,3,4-thiadiazin-4-one (compound No. 377):

0.9g(19% 수율)을 얻었다.In a similar manner to Example 51, 2.4 g (0.006 mol) of 1,3,5-tris (2,4-dimethylphenyl) -hexahydro-s-triazine, 1.8 g (0.009 mol) of trichloromethylchloroformate The reaction was carried out using 2.1 g (0.016 mol) of 1-methyl-3-isopropylthiourea and 15 g of an aqueous 10% sodium hydroxide solution. After the reaction was completed, n-hexane insolubles were removed by filtration, and n-hexane was removed from the filtrate by steam. This residue was dissolved in ether and hydrogen chloride gas was passed through ether oil. The ether-insoluble oil was separated by distillation and deposited at the bottom. After the solvent was removed, excess alkaline was added to the oily solution and extracted with benzene. The benzene layer was washed with water, dehydrated and concentrated to give a colorless oil.

0.9 g (19% yield) was obtained.

로서 2이소프로필이미노-3-이소프로필-5-(2,4-디메틸페닐)테트라하이드로-1.3.5-티아디아진-4-온(제 378번 화합물) 1.2g(22% 수율)을 얻었다.In a similar manner, 2.4 g (0.006 mol) of 1,3,5-tris (2,4-dimethylphenyl) -hexahydro-s-triazine, 1.8 g (0.009 mol) of trichloromethyl chloroformate, 1, 2.5 g (0.0016 mol) of 3-diisopropylthiourea and 15 g of 10% aqueous sodium hydroxide solution have the following structural formula, and are a pale yellow oil.

1.2 g (22% yield) of 2isopropylimino-3-isopropyl-5- (2,4-dimethylphenyl) tetrahydro-1.3.5-thiadiazin-4-one (compound No. 378) Got it.

Similarly, 2.4 g (0.006 mol) of 1,3,5-tris (2,4-dimethylphenyl) -hexahydro-s-triazine, 1.8 g (0.009 mol) of trichloromethylchloroformate, 1-iso 2.9 g (0.0016 mole) of propyl-3-t-butylthiourea and 15 g of 10% aqueous sodium hydroxide solution have the following structural formula, and 2-t-butylimino- is a white crystal that melts at 99-100 ° C. 1.0 g (18% yield) of 3-isopropyl-5-12,4-dimethylphenyl) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 379) was obtained.

In a similar manner, 3.3 g (0.007 mol) of 1,3,5-tris (2-methyl-4-chlorophenyl) -hexahydro-s-triazine, 2.0 g (0.01 mol) of trichloromethylchlorophosphomate, 3.2 g (0.018 mol) of 1-isopropyl-3-t-butylthiourea and 18 g of 10% aqueous sodium hydroxide solution have the following structural formula, 2-t-butyl as white crystals melting at 122-123 ° C. 0.5 g (7% yield) of imino-3-isopropyl-5-12-4-dimethylphenyl) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 379) was obtained.

로서 2-메틸이미노-3-메틸-5-(2,6-디메틸페닐)-테트라하이드로-1, 3,5-티아디아진-4-온(제389번 화합물 0.6g(12% 수율)을 얻었다.Similarly, 2.7 g (0.02 mol) of N-methylene-2,6-dimethylaniline, 2.0 g (0.02 mol) of trichloromethylchloroformate and 2.0 g (0.02 mol) of 10% aqueous sodium hydroxide solution Colorless oily substance having the following structural formula

2-methylimino-3-methyl-5- (2,6-dimethylphenyl) -tetrahydro-1,3,5-thiadiazin-4-one (compound No. 389 (0.6 g, 12% yield) Got.

Similarly, 2.7 g (0.02 mol) of N-methylene-2,6-dimethylaniline, 2.0 g (0.01 mol) of trichloromethylchloroformate, 3.3 g (0.019) of 1-isopropyl-3-t-butylthiourea Mole) and 18 g of 10% aqueous sodium hydroxide solution and have the following structural formula and are 2-t-butylimino-3-isopropyl-5- (2,6-dimethylphenyl as white crystals, melting at 103-104 ° C. 0.3 g (7% yield) of) -tetrahydro-1.3.5-thiadiazin-4-one (compound No. 388) was obtained.

Example 54

2-Isopropylimino-3-methyl-5- (2,4-diethylphenyl) -tetrahydro-1,3,4-thiadiazin-4-one (compound No. 393):

A 1.6 g (0.01 mol) solution of N-methylene-2,6-diethylaniline dissolved in 20 ml of benzene was added dropwise while stirring to 10 ml of toluene containing 1.2 g of phosgene. After stirring for 10 minutes, 1.3 g (0.01 mol) of 1-methyl-3-isopropylthiourea was added to the mixture and heated to reflux for 1 hour. The reaction mixture was mixed with 100 ml of water and the benzene layer was removed. The aqueous layer was made alkaline with 5 ml of 30% potassium hydroxide solution and extracted with 1000 ml of benzene. The benzene layer was washed with water, dried and concentrated to give a viscous oil. The oil was recrystallized from isopropyl alcohol to give 1.7 g (56% yield) of white crystals melting at 106-107 ° C.

Example 55

2-isopropylimino-3-isopropyl-5- (2,6-diethylphenyl) -tetrahydro-1,3,4-thiadiazin-4-one (compound No. 395)

A solution of 1.6 g (0.01 mol) of N-methylene-2,6-diethylaniline dissolved in 10 ml of benzene was added to 10 ml of benzene containing 1.1 g of trichloromethylchloroformate while stirring. After stirring for 10 minutes, 1.6 g (0.01 mol) of 1,3-diisopropylthiourea dissolved in 20 ml of benzene was added to the mixture and heated at reflux with stirring for 1 hour. The reaction mixture was mixed with 100 ml of water and stirred thoroughly. The aqueous layer was separated and mixed with 5 ml of 0% aqueous potassium hydroxide solution to deposit an oily substance, which was extracted with benzene. The benzene layer was washed with water, dried and concentrated to give a viscous oily product, which was recrystallized from isopropanol-n-hexane (8: 2) to obtain 1.4 g (40% yield) of white crystals melting at 89-90 ° C. .

Example 56

2-t-Butylimino-3-ethyl-5-phenyl-tetrahadro-1,3,5-thiadiazin-4-one (compound No. 131):

A solution of 46 g of aniline dissolved in 250 ml of ethanol was mixed with 75 ml of 37% formalin and stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration, washed with ethyl alcohol and recrystallized with hot benzene to give 1,3,5-triphenyl-hexahydro-s-triazine which melted at 130-133 ° C. 1.0 g (0.0033 mol) of 1,3,5-triphenyl-hexahydro-s-triazine dissolved in 20 ml of tetrahydrofuran while stirring in a solution of 1.2 g of trichloromethylchloroformate dissolved in 10 ml of benzene. The solution was added dropwise, followed by addition of a solution of 1.6 g of 1-ethyl-3-t-butylthiourea dissolved in 20 ml of benzene, followed by 8 ml of 15% aqueous potassium hydroxide solution. The reaction mixture was heated to 40-50 ° C. and stirred for 5 hours. The reaction mixture was poured into water, and the separated benzene layer was washed with water and then dried. The crude crystals obtained by removing benzene from distillation were recrystallized from isopropyl alcohol to obtain 1.0 g (38% yield) of white crystals melting at 93-94 ° C.

In a similar manner, 1.0 g of 1,3,5-triphenylhexahydro-s-triazine, 1.1 g of trichloromethylchloroformate and 1.7 g of 1-isopropyl-3-t-butylthiourea were reacted as follows. 2-t-butylimino-3-isopropyl-5-phenyl-tetrahydro-1,3,5-thiadiazin-4-one as a white crystal having the same structural formula and melting at 106-107 캜 1.2 g (40% yield) of Compound 145 was obtained.

The compounds of the present invention were mixed with the adjuvant in various compositions according to the following formulation method. The form and proportions of the compounds and adjuvants and the form of the composition may vary as needed. Methods of mixing and using the compositions are similar to those known in the art. In the following examples, all parts are by weight.

Example 57

The following components were uniformly mixed to prepare an emulsifier.

Example 58

The powder was prepared by uniformly mixing the following ingredients.

Example 59

The following ingredients were mixed uniformly, then thoroughly kneaded with an appropriate amount of water, ground and dried to form granules.

Example 60

The following components were uniformly mixed to prepare a hydration component.

Example 61

An oil spray agent was prepared by mixing the following components.

Example 62

The following components were dissolved in a suitable solvent, sprayed onto at least 95 parts of granular clay (1048 mesh, Tyler Standardad Sieve), and then dried to prepare granules.

Example 63

The following components were uniformly mixed to prepare an emulsifying thickener.

Example 64

The powder was prepared by uniformly mixing the following ingredients.

Example 65

The following ingredients were uniformly mixed, thoroughly kneaded with an appropriate amount of water, ground, and dried to form granules.

Example 66

The following ingredients were uniformly mixed to prepare a water-soluble powder.

Example 67

An oil spray agent was prepared by mixing the following components.

Example 68

A solution of 3 parts of compound No. 87 dissolved in a suitable solvent was sprayed into 97 parts of granular clay (10-48 mesh, Tyler Standardad sieve particle size), and then dried to prepare a granule.

Example 69

The following components were uniformly mixed to prepare an emulsifying thickener.

Example 70

The powder was prepared by uniformly mixing the following ingredients.

Example 71

The following ingredients were uniformly mixed, thoroughly kneaded with an appropriate amount of water, ground, and dried to prepare granules.

Example 72

The following ingredients were uniformly mixed to prepare a water-soluble powder.

Example 73

An oil spray agent was prepared by mixing the following components.

Example 74

The following components were dissolved in a suitable solvent, sprayed into 95 parts of granular clay (10 48 mesh, Tylustanad sieve particle size), and dried to prepare an isolation agent.

[Test Example 1]

Insecticidal Effects of Nilaparvata lugens Stahl on Larvae

Test Methods :

Five rice seedlings at 1.5 leaf stage were soaked in a 400 ppm test composition for 30 seconds. After air drying, seedlings were placed in glass tubes containing 1 ml of water and infected with 3/5 larvae. After leaving the glass tube in a room temperature cabinet at 25 ° C., lethal-and-survival was observed around 5 or 7 days. Mortality was calculated from the results of the three replicates. The results obtained are shown in Table 1.

TABLE 1

No. 2 compound 88: data 7 days after treatment

Compound 126 No. 428: Data after 5 days of treatment

[Test Example 2]

Insecticidal Effects on Larvae of Sogatella furcifera Horvath

Test Methods :

Five rice seedlings at 1.5 leaf stage were soaked in a 400 ppm test composition for 30 seconds. After air drying, seedlings were placed in a glass tube containing 1 ml of water and infected with 1/5 larvae. In the case of 7 days after the glass tube was left in a room temperature cabinet at 25 ° C., lethality and survival rates were observed. Mortality was calculated from the results of the three replicates. The results obtained are shown in Table 2.

TABLE 2

[Test Example 3]

Effect on Tetranychus urticae koch

Test Method: A double-winged spider mite was infected with potted beans in a greenhouse. The next day, the 1000 ppm test composition was sprayed into the beans with a spray gun. Two or five days after the task, mortality was calculated by examining lethal-and-survival rates.

The results obtained are shown in Table 3.

TABLE 3

No. 2 to No. 88 compound: data 2 days after treatment

188-3428 Burr compound: data after treatment days

[Test Example 4]

Effect on Panonychus citri McGregor.

Test Methods :

The test was done by the Rothamstead method. The test composition was sprayed onto grape leaves infected with red mandarin aphids with a spray gun. After spinning, the grapes were left in a room temperature cabinet at 25 ° C. Two days after the treatment, the number of surviving ticks was counted to determine mortality. The results obtained are shown in Table 4.

TABLE 4

[Test Example 5]

Effects of Nephotettix cincticeps uhler on larvae.

Test Methods :

Five rice seedlings at 1.5 leaf stage were soaked in a 400 ppm test composition for 30 seconds. After air drying, the seedlings were placed in a glass tube containing 1 ml of water and infected with a 2/5 larval stage cicada larvae. The glass tube was left to stand in a 25 degreeC room temperature cabinet. Ten days after the treatment, the lethal-and-survival rate was examined and mortality was calculated by repeating the test rate three times.

The results obtained are shown in Table 5.

TABLE 5

[Test Example 6]

Insecticidal effect on the larvae of culex pipiens pallens Coquillett

Test Methods :

In a 200 ml beaker, 100 ml of the test composition diluted to 10 ppm concentration with deionized water was placed. The test composition was infected with a 1/20 larva stage collector and the beaker was covered with one Japanese paper. The beaker was covered with a piece of Japanese paper. The beakers were kept in a room temperature cabinet at 25 ° C. After 5 days of treatment, mortality was calculated by examining lethal-and-survival rates. The results obtained are shown in Table 6.

TABLE 6

[Test Example 7]

List of insecticidal effects on the Tri- bleu-Tribolium castaneum Herbst adult.

Test Methods :

A 7 ml 400 ml test composition was introduced into a 9 cm pepper saucer covered with a filter paper piece. Ten adult rustred flour beetles were placed in a pepper dish and left in a 25 ° C room temperature cabinet. After 24 hours, mortality was calculated by examining lethal-and-survival rates. The results obtained are shown in Table 7.

TABLE 7

[Test Example 8]

Insecticidal Effects on 28-point Radial Beetles (Epilachna vigintioctopunctana fabricius)

Test Methods :

The leaves of tomato grown in the greenhouse were immersed in a test composition of 100 ppm concentration for 30 seconds, and 1 ml of water was added to the covered pepper saucer and the tomato leaves were treated three times. Peanuts dishes, infected with 28 point radiobites of the 2/7 larval stage, were left in a 25 ° C room temperature cabinet. Five days after the treatment, lethality and survival were checked, and the two trials were repeated to calculate mortality. The results obtained are shown in Table 8.

TABLE 8

[Test Example 9]

Insecticidal Effects on the Larva of Togo hemipterus Scott

Test Methods :

1 ml of 10 ppm test composition was added to the glass tube (1.6 cm inside diameter and 9 cm length), and the absorption surface was side, and it was covered with five rice seeds and one Japanese paper. The glass tubes were kept in a 25 ° C. room temperature cabinet and mortality was calculated by repeating the test three times by examining lethal-and-survival rates 5 days after treatment. The results obtained are shown in Table 9.

TABLE 9

[Test Example 10]

Insecticidal Effects on Diamond Larva (Plutilla Xylostella Linnie)

Test Methods :

A test composition of 400 ppm concentration was sprayed with a spray gun to potted cabbage in a greenhouse. After air drying, cabbages were placed in a greenhouse infected with 1/10 larval stage diamond-white moths. Three days after treatment, lethal-and-survival rates were examined and three trials were performed to calculate mortality. The results obtained are shown in Table 10.

TABLE 10

Claims (1)

Tetrahydro-1,3,5-thiadiazine of the following general formula (I) characterized by reacting filtrated carbamoyl of the following general formula (II) with thiourea of the following general formula (III) in the presence of a base: 4- is a method for producing a derivative.

(Wherein in the formula R ^1, R ² and R ³ may be the same or different and may be a good or different and are each C _1~ C ₈ alkyl group, an allyl group, a cycloalkyl group of C ₃ -C _6, 3~6 carbon atoms in total Having one or more substituents selected from the group consisting of an alkoxyalkyl group, a benzyl group, a phenyl group or a substituent having a C ₁ -C ₄ alkyl group, a nitro group, a halogen atom, a C ₁ -C ₄ alkoxy group and a trifluoromethyl group A substituted phenyl group, R ¹ represents a hydroxyphenyl group, R ² represents a hydrogen atom or a furfuryl group, and R ³ may represent a hydrogen atom).