JPH0635442B2 - Process for producing thiocarbamate derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate.

The compound is useful as a medicine such as a remedy for athlete's foot, an agricultural chemical such as a herbicide, or an intermediate raw material thereof. In particular, O-2-naphthyl N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate is known to be a compound useful as an active ingredient of agricultural chemicals, especially herbicides for paddy fields.

(Prior Art) Conventionally, as a method for producing an O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate, for example, N- (6-methoxy-2-pyridyl represented by the formula (A) is represented. ) -N-methylthiocarbamoyl halide and 2-naphthol, or 6-methoxy-2-methylaminopyridine and 2-naphthylhalothioformate represented by the formula (B) are reacted in the presence or absence of an inert solvent. It is known how to do this.

(JP-A-58-159461) (X represents a halogen atom.) (Problems to be solved by the invention) However, it is very difficult to industrially obtain the compounds represented by the general formulas (A) and (B) used as raw materials in the above reaction. Is.

Because the compound represented by the general formula (A) is a thiocarbamoyl halide group The compound represented by the general formula (B) is a thiocarbanyl halide group. However, the highly toxic thiophosgene must be used to obtain compounds containing these groups. For example, the compound represented by the general formula (A) is 6-methoxy-2-
Methylaminopyridine must be reacted with thiophosgene and the compound represented by the general formula (B) must be reacted with 2-naphthol and thiophosgene under strict control in terms of occupational safety and health. This is very troublesome for industrial production. At this time, since the physical properties of the target compound and the thiocarbamate of the following structural formula, which are by-produced in each reaction, are very similar, separation is difficult and it is very difficult to obtain the target product in high purity.

As is clear from the above reason, the conventional technique is not a suitable method for industrially producing O-2-naphthyl N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate.

As a result of diligent studies on the method for industrially inexpensively and safely producing the compound, the present inventors have eliminated the above-mentioned drawbacks,
The present invention has been completed by finding a new process using 6-alkoxy-2-alkylaminopyridine as a raw material.

(Means for Solving Problems) That is, the gist of the present invention is that an industrially advantageous O-aryl N is used.
In providing a method for producing-(6-alkoxy-2-pyridyl) -N-alkylthiocarbamate, carbon disulfide is reacted with 6-alkoxy-2-alkylaminopyridine in the presence of a strong base as shown in the following formula. To give N- (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamic acid alkali metal salt, and subsequently add 2,4 to this salt.
-O-aryl characterized by reacting with dinitrohalobenzene to give S- (2,4-dinitrophenyl) N- (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamate, which is reacted with phenols This is a method for producing N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate.

That is, the feature of the present invention is represented by the general formula (I) using the compound of the general formula (II) as a starting material as shown in the above reaction formula, and the two intermediates of the general formula (III) and the general formula (V). O-aryl N
To produce a-(6-alkoxy-2-pyridyl) -N-alkylthiocarbamate.

According to the method of the present invention, it is easy to separate 2,4-dinitrothiophenol, which is a by-product together with the desired product in the final stage of the reaction, and this is also a useful compound as an intermediate raw material for medicines, agricultural chemicals and the like. There is an advantage that can be utilized.

Still another feature of the present invention is that two useful sulfur-containing compounds can be simultaneously produced in one reaction without wasting a sulfur source of carbon disulfide.

As the strong base used for the dithiocarbamylation of the present invention, sodium hydride, sodium amide, lithium aluminum hydride, sodium borohydride, lithium amide, lithium hydride, potassium hydride and the like can be used.
Good results are obtained when both carbon disulfide and the strong base are used in a 1.0-1.1 times molar amount with respect to 6-alkoxy-2-alkylaminopyridine. If it is less than 1.0 times by mole, the yield is low, and if it exceeds 1.1 times by mole, it is uneconomical without any significant effect. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, N.I. A polar solvent such as N-dimethylformamide or dimethyl sulfoxide can be used.

The reaction temperature is usually about 0 ° C to about 30 ° C, preferably about 5 ° C.
Keep in the range of about 20 ° C. If the temperature is too low, the reaction rate will be slow, and if it is too high, a side reaction will occur, resulting in a decrease in yield. The N- (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamic acid alkali metal salt obtained by the reaction can be isolated, but it can be directly used in the next step as it is without isolation. It is possible.

Then, S- (2,4-dinitrophenyl) N- (6
-Alkoxy-2-pyridyl) N-alkyldithiocarbamates can be prepared. 2,4-dinitrochlorobenzene as 2,4 dinitrohalobenzene,
2,4-dinitrobromobenzene, 2,4-dinitroiodobenzene and the like can be used. 2,4-dinitrohalobenzene is N- (6-alkoxy-2-pyridyl) -N-
1. For alkali metal alkyldithiocarbamic acid
Good results are obtained by using 0 to 1.1 times mol. 1.0
If it is less than twice the molar amount, the yield is low, and if it exceeds 1.1 times the molar amount, there is no significant effect and it is uneconomical.

As the solvent, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, and polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide can be used. The reaction temperature is maintained in the range of about 0 ° C to about 50 ° C, preferably about 5 ° C to about 30 ° C. If the temperature is too low, the reaction rate will be slow, and if it is too high, side reactions will occur, resulting in a decrease in yield. S- obtained by the reaction
The (2,4-dinitrophenyl) N- (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamate can be easily isolated. Then, the dithiocarbamate derivative obtained by the above reaction is reacted with a phenol to easily obtain the desired O-aryl.
N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamates can be prepared. As the phenols, almost all phenols such as the phenol represented by the general formula (C) and various nucleus-substituted phenols, the naphthol represented by the general formula (D) and various nucleus-substituted naphthols can be used.

Y ₁ , Y ₂ and Y ₃ do not depend on each other and are hydrogen, a halogen atom,
The phenols showing a carboxyl group, an alkyl group, an alkoxy group, an acetyl group, etc. are S- (2,4-dinitrophenyl)
Good results can be obtained by using 1.0-1.1 times mol of N- (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamate. If it is less than 1.0 times the molar amount, the yield will be low, and if it exceeds 1.1 times the molar amount, there will be no significant effect and it will be uneconomical.

When S- (2,4-dinitrophenyl) N- (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamate and phenols are reacted with each other, an equivalent amount of a basic substance is added to allow the reaction to proceed smoothly. As the basic substance, alkali hydroxide such as sodium hydroxide or potassium hydroxide,
Sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Alkali carbonates such as potassium hydrogen carbonate, strong bases such as sodium hydride, lithium hydride and sodium amide, and tertiary amines such as triethylamine, dimethylaniline and pyridine can be used.

As the reaction solvent, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, chlorobenzene, chloroform and methylene chloride. , Halogenated hydrocarbons such as dichloroethane, and the like. In particular, good results are obtained when N, N-dimethylformamide or a mixed system of N, N-dimethylformamide and the above reaction solvent is used.

The reaction temperature is about 20 ° C to about 100 ° C, preferably about 30 ° C.
Keep in the range of ~ 80 ° C. If the temperature is too low, the reaction rate will be slow, and if it is too high, side reactions will occur, resulting in a decrease in yield.

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example-1 42.0 g of 60% sodium hydride under a nitrogen atmosphere
(1.05 mol), tetrahydrofuran 177 g 2
Into a four-necked flask, 492 g of a tetrahydrofuran solution containing 138.0 g (1.00 mol) of 6-methoxy-2-methylaminopyridine was added dropwise at room temperature, and further 1 hour under reflux while releasing hydrogen out of the system. Stir for 30 minutes.

Next, 79.8 g of carbon disulfide (1.
(05 mol) was added dropwise, and the mixture was further stirred at room temperature for 1 hour.
After that, tetrahydrofuran was partially distilled off, the reaction product was concentrated, diethyl ether was added, and the precipitated crystals were separated, washed and dried to give a pale yellowish white N- (6-methoxy-2-pyridyl) -N-methyldithiocarbamic acid. Sodium 22
7.3 g (yield 96.3%) was obtained.

Next, 112.1 g (0.47 g) of sodium N- (6-methoxy-2-pyridyl) -N-methyldithiocarbamate
5 mol) was dissolved in 400 g of ethanol, and 2,4
600 g of an ethanol solution containing 101.1 g (0.499 mol) of dinitrochlorobenzene was added dropwise at around 10 ° C, and the mixture was further stirred at room temperature for 2 hours. The precipitated crystals were separated, washed with water and dried to give yellow crystals of S- (2,4-dinitrophenyl) N- (6-methoxy-2-pyridyl)-.
168.2 g of N-methyldithiocarbamate (yield 9
3.2%). The melting point of this product is 112.4 ° C to 1
It was 13.7 ° C.

Next, 47.6 g (0.20 mol) of S- (2,4-dinitrophenyl) N- (6-methoxy-2-pyridyl) -N-methyldithiocarbamate, 2-naphthol 28.
8 g (0.20 mol), N, N-dimethylformamide 150 g, 95% sodium methylate 11.4 g
(0.20 mol) was charged into a 14-necked flask and heated to 50 ° C.
It was stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into cold water, and the product was extracted with benzene. After washing the benzene solution with water, benzene was distilled off under reduced pressure. The residue was recrystallized from methanol to obtain 49.2 g of white crystals.

This product was analyzed by elemental analysis, nuclear magnetic resonance absorption spectrum, infrared absorption spectrum, and physical properties as shown in O-2-
Naphthyl N- (6-methoxy-2-pyridyl) -N-
It was identified as methylthiocarbamate. The yield is S-
(2,4-Dinitrophenyl) N- (6-methoxy-
7 for 2-pyridyl) -N-methylthiocarbamate
The ratio was 5.9% and 68.1% with respect to 6-methoxy-2-methylaminopyridine as a starting material.

Elemental analysis value (as C ₁₈ H ₁₆ N ₂ O ₂ S) Nuclear magnetic resonance absorption spectrum (CDCl ₃ , internal standard TMS) δ-ppm δ 3.75 (3H S) δ 3.92 (3H S) δ 6.58-6.66 (1H, d) δ 6.89-7.87 (9H, m) infrared absorption spectrum (KBr method) cm ^-1 1610, 1465, 1430, 1380, 1335 1270, 1180, 1040, 820, 750 GC-MS molecular weight 324 Physical properties Melting point 95.6 ° -96.5 ° C Solubility benzene, chloroform, Easily soluble in N, N-dimethylformamide.

Soluble in lower alcohol. Insoluble in water and hexane.

Examples 2 to 12 Alkyl group of starting material of general formula (II) used in (step A), strong base, solvent, halogen of compound of general formula (IV) used in (step B), solvent, (step C) Formula (VI) used in
The reaction was carried out under the same conditions as in Example 1 by changing the aryl group, basic substance, and solvent of the compound of Example 1 as shown in Table 1 to obtain the corresponding O-aryl-N- (6-alkoxy-2-pyridyl) -N. -Alkyl thiocarbamate was obtained. As in Example 1, they were identified by elemental analysis values, molecular weight by GC-MS, nuclear magnetic resonance absorption spectrum, infrared absorption spectrum, physical properties and the like. The data obtained are shown in Table 2.

(Effect of the Invention) The method of the present invention is useful as an intermediate for pharmaceuticals and agricultural chemicals O-aryl N- (6-alkoxy-2-pyridyl) -N-
In the production of alkyl thiocarbamates, 6-
It is intended to provide a new production method comprising a series of steps starting from the reaction of alkoxy-2-alkylaminopyridine with carbon disulfide. In each step, the reaction proceeds under mild conditions and a high-purity target product can be obtained in good yield. One atom of sulfur in carbon disulfide is recovered as a thiophenol derivative in the final step.
It is useful as an intermediate raw material for agricultural chemicals.

Claims (8)

[Claims] 1. A general formula (R ₁ and R ₂ do not depend on each other, and the C ₁ -C ₃ alkyl group is Ar.
Represents an aryl group. ) O-aryl-N- (6-alkoxy-2)
-Pyridyl) -N-alkylthiocarbamate is prepared by the method of the general formula (R ₁ and R ₂ represent the same alkyl group as in the general formula (I).) The 6-alkoxy-2-alkylaminopyridine represented by the general formula (I) is reacted with carbon disulfide in the presence of a strong base, (R ₁ and R ₂ represent the same alkyl group as in the general formula (I), and M represents an alkali metal.) N- (6-alkoxy-2-pyridyl)-
A step of producing an alkali metal salt of N-alkyldithiocarbamic acid, and then adding the alkali metal salt represented by the formula (III) to the general formula (X represents a halogen atom.) 2,4-dinitrohalobenzene represented by the formula: (R ₁ and R ₂ represent the same alkyl group as in the general formula (I).) S- (2,4-dinitrophenyl) N-
A step of producing (6-alkoxy-2-pyridyl) -N-alkyldithiocarbamate, and then the dithiocarbamate derivative represented by the formula (V) is represented by the general formula Ar-OH (VI) (Ar represents an aryl group). Reacting a phenol represented by the formula (1) in a solvent to produce an O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate represented by the general formula (I). And a method for producing an O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate. 2. R ₁ and R _{2 of the} general formulas (I), (II), (III) and (IV).
The method according to claim (1), wherein both are methyl groups. 3. The method according to claim 1, wherein Ar in the general formula (I) is a 2-naphthyl group. 4. The method according to claim 1, wherein Ar in the general formula (I) is a m-tert-butylphenyl group. 5. The method according to claim 1, wherein M in the general formula (III) is sodium. 6. The method according to claim 1, wherein X in the general formula (IV) is chlorine. 7. The method according to claim 1, wherein sodium hydride is used as a strong base in the production of the alkali metal salt represented by the general formula (III). 8. A method for reacting a dithiocarbamate derivative represented by the general formula (V) with a phenol represented by the general formula (VI), wherein N, N-dimethylformamide is used as a solvent. The method described.