JPS6248667A - Production of thiocarbamate derivative - Google Patents

Abstract

PURPOSE:To industrially and safely obtain the titled compound useful as a medicine, agricultrual chemical or intermediate therefore at a low cost, by starting from a 6-alkoxy-2-alkylaminopyridine as a starting raw material and passing through respective two specific intermediates. CONSTITUTION:A compound expressed by formula I (R1 and R2 are 1-3C alkyl) is reacted with carbon disulfide in the presence of a strong base to give a compound expressed by formula II (M is alkali metal), which is then reacted with a compound expressed by formula III (X is halogen) to afford a compound expressed by formula IV. The resultant compound expressed by formula IV is then reacted with a compound expressed by the formula Ar-OH (Ar is aryl) in a solvent to industrially and advantageously give the aimed compound. A compound, expressed by formula VI and formed as a by-product together with the aimed compound in the final stage can be readily separated and utilized as an intermediate for medicines and agricultural chemicals, etc. Therefore, two useful sulfur-containing compounds can be simultaneously produced by one reaction without wasting sulfur sources, e.g. carbon disulfide, according to this method.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing 0-aryl N-(6-alkoxy-2-pyridyl)-N-alkylthiocarbamates.

The compound is useful as a medicine such as a treatment for athlete's foot, a pesticide such as a herbicide, or an intermediate raw material thereof. Among them, 0-2-naphthyl N-(6-medoxy-2-pyridyl)-N-methylthiocarbamate is known to be a useful 46 compound as an active ingredient in herbicides for mulberry, especially for paddy fields. .

(Prior art) (The main method is a method for producing 0-aryl N-(6-alkoxy-2-pyridyl)N-alkylthiocarbamate. pyridyl)-N-methylthiocarbamoyl halide and 2-naphthol.

Alternatively, a method is known in which 6-medoxy-2-methylaminopyridine and 2-naphthylhalothioformide represented by the formula (B) are reacted with 3b or 2-y in the presence of an inert solvent.

(Machi 1) C1 Showa 58-159461
It is very difficult to industrially obtain the compound represented by B).

This is because the compound represented by the general formula 4 has a thiocarbamoyl halide group ()N-C-X) in the general formula (B).
The compound represented by has a thiocarbonyl halide group (-C
-X), but in order to obtain a single compound with these groups, highly toxic thiophosgene must be used. For example, a compound represented by the general formula (N) reacts 6-medoxy-2-methylaminopyridine with thiophosgene, and a compound represented by the general formula (B) reacts 2-naphthol with thiophosgene, each under strict control in terms of occupational safety and health. This is very troublesome for industrial production.In addition, in this case, the physical properties of the target product are very similar to the thiocarbamate of the following structural formula that is produced as a by-product in each reaction. Therefore, it is difficult to separate 0-2-naphthyl N-(
This method cannot be said to be suitable for industrially producing 43-methoxy-2-pyridyl)-N-methylthiocarbamate.

The present inventors have intensively investigated a method for producing the compound in an inexpensive and completely industrial manner that eliminates the above drawbacks, and uses 5-alkoxy-2-alkylaminopyridine as a raw material. This invention is based on the discovery of a new process for achieving this.

(Means for Solving the Problems) The gist of the present invention is to provide industrially advantageous O-aryl N
-(6-alkoxy-2-pyridyl)-N-alkylthiocarbamate! l! When preparing the manufacturing method, F
As shown in the formula, 6-alkoxy-2-furkylaminopyridine is reacted with carbon disulfide in the presence of a strong base, and N-
(6-alkoxy-2-pyridyl)-N-alkyldithiocarbamic acid alkali gold scrap salt, and then this salt was reacted with 2゜4-dinitrohalobenzene.
゜4-dinitrophenyl)N-(6-alkoxy-2-
O-aryl N-(6-alkoxy-2-pyridyl)-N-, which is characterized by reacting phenol with the O-aryl N-(6-alkoxy-2-pyridyl)-N-
Alkylthiocarbame general formula (V)
-0 formula (1), that is, the feature of the present invention is that as shown in the above reaction formula, general formula (II) is used as a starting material, and general formula (2)
, the two intermediates of the general formula (V) are combined with the formula 18 (1
) to O-aryl represented by (6-alkoxy-2
-pyridyl)-N-alkylthiocarbamate.

According to the method of the present invention, it is easy to separate 2,4-dinitrothiophenol, which is produced as a by-product along with the target product in the final stage of the reaction, and this compound is also useful as an intermediate raw material for pharmaceuticals, agricultural chemicals, etc. Therefore, there are advantages that can be utilized.

Another feature of the present invention is that two useful sulfur-containing compounds can be simultaneously produced by one reaction without wasting the sulfur source of carbon sulfide.

As the strong base C used in the dithiocarbamylation of the present invention, sodium hydride, sodium amide, lithium aluminum hydride, sodium borohydride, lithium amide, lithium hydride, potassium hydride, etc. can be used. All carbon disulfide 9 strong bases are 1. Good results are obtained when using 0 -1.1 times the molar amount. If it is less than 1.0 times the mole, the yield will be low and if it exceeds 1.1 times the mole, Celsius has no significant effect and is uneconomical.

As the solvent, ethers such as diethyl ether, 9-trahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide can be used.

The reaction temperature is usually about 0'C to about 30'C, preferably about 50'C.
Keep in the range of °C to about 20 °C. If the temperature is too low, the reaction rate will be slow; if the temperature is too high, side reactions will occur, causing a decrease in yield. Although it is also possible to isolate the N-(6-alkoxy-2-pyridyl)-N-alkyldithiocarbamic acid alkali metal salt obtained in the reaction, the reaction solution should be used in the next step without isolation. is also possible.

Next, by reacting with 2.4dinitrohalobenzene, 8-(2,4-dinitrophenyl)N-
(6-Alkoxy-2-pyridyl)N-alkyldithiocarbamates can be produced. As the 2.4-dinitrohalobenzene, 2,4-dinitrochlorobenzene, 2,4-dinitrobromobenzene, 2,4-dinitroiodobenzene, etc. can be used. 2.4-dinitrohalobenzene is N-(5-alkoxy-2-pyridyl)
Good results can be obtained by using 1.0 to 1.1 times the mole of -N-alkyldithiocarbamic acid alkali metal salt.

If it is less than 1.0 times the mole, the yield will be low, and if it exceeds 1.0 times the mole, there will be no significant effect and it will be uneconomical.

Examples of solvents include lower alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran and dioxane, and acetone.

Ketones such as methyl ethyl ketone, polar solvents such as N,.N-dimethylformamide, and dimethyl sulfoxide can be used. The reaction temperature is kept in the range of about 0"C to about 50°C, preferably about 30°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, causing a decrease in yield. 8-(2,4-dinitrophenyl)N-(6-alkoxy-2-pyridyl)-N obtained by the reaction
-Alkyldithiocarbamates can be easily injected. Next, the desired O-aryl N-(6-alkoxy-2-pyridyl)-N-alkylthiocarbamate can be easily produced by reacting the dithiocarbamate derivative obtained by the reaction described in θσ with a phenol. can. As for phenols, C is the phenol represented by the general formula (C) and phenol with various nuclei converted to it, naphthol represented by the general formula Can be done.

Yl, Y2. Phenols in which Yl independently represents hydrogen, a halogen atom, a carboxyl group, an alkyl group, an alkoxy group, an acetyl group, etc. are 8-(2,4-dinitrophenyl)N
Good results can be obtained by using 1.0 to 1.1 times the mole of -(6-alkoxy-2-pyridyl)-N-furkyldithiocarbamate. If it is less than 1.0 times the mole, the yield is low, and if it exceeds 1.1 times the mole, °C has no significant effect and is uneconomical.

When reacting 5-(2,4-dinitrophenyl) N-(6-alkoxy-2-pyridyl)-N-alkyldithiocarbamate with phenols, the reaction proceeds smoothly by adding our basic substance. .C as a basic substance
are alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, strong bases such as sodium hydride, lithium hydride, and sodium amide, triethylamine, Tertiary amines such as dimethylaniline and pyridine can be used.

The reaction solvent C is a lower alcohol such as methanol, ethanol, isopropanol, etc. Ethers such as trahydrofuran and dioxane, and benzene.

Aromatic hydrocarbons such as toluene and xylene, acetone,
Examples include ketones such as methyl ethyl ketone, halogenated hydrocarbons such as chlorobenzene, chloroform, methylene chloride, and dichloroethane. N, N-
Good results can be obtained by using dimethylformamide or a mixture of dimethylformamide and the above reaction solvent.

The reaction temperature is about 20°C to about 100°C, preferably about 3
The range is from 0°C to about 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 low yield.

EXAMPLES 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 60% sodium hydride 42.0f (1
,05 mol), tetrahydrofuran 177F to 214.
Pour into a double flask and add 188% of 6-medoxy-2-methylaminopyridine. 492 g of a tetrahydrofuran solution containing 00 moles of oll) was added dropwise at room temperature, and the mixture was further stirred under reflux for 1:1 to 130 minutes while releasing hydrogen from the system.

Next, cool the carbon disulfide at around 10°C to 79.8f (1
, 05 mol) was added dropwise, and the mixture was further stirred at room temperature for 1 hour. After that, some of the tetrahydrofuran was distilled off, the C reaction product was concentrated, diethyl ether was added, and the precipitated crystals were separated by P.
Washed and dried yellowish white sodium N-(6-medoxy-2-pyridyl)-N-methyldithiocarbamate 22
7.3 g (yield 96.3%) was obtained.

Next, sodium N-(6-medoxy-2-pyridyl)-N-methyldithiocarbamate 112°110.47
Dissolve 5 mol) in 40 ethanol (1') and add 2,
600g of ethanol solution containing 101.1f (0,499 mol) of 4dinitrochlorobenzene was added before and after to'c.
C dropwise was added and the mixture was further stirred at room temperature for 2 hours. Thereafter, the precipitated crystals were separated from P, washed with water, and dried to form M-colored crystals of 8-(2,4
-dinitrophenyl)N-(6-medoxy-2-pyridyl)-N-methyldithiocarbamate 168.2y (yield 93.2%) was obtained. The melting point of this substance is 112.4℃
~113,'7°C.

Then 8-(2,4-dinitrophenyl) N-(6-medoxy 2-pyridyl)-N-methyldithiocarbamate 47L 6 f (0,20 mol) 2-naphthol 28.810.20 mol) N,N -dimethylformamide 150f, 95% sodium methylate 11.4F (
0.20 mol) in 144 liter flask Naruko preparation 50
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, the benzene was distilled off under reduced pressure. The residue was diluted with methanol. Recrystallization gave white crystals of 49.2 F.

This product is 0-2 based on the elemental analysis value, nuclear magnetic resonance absorption spectrum, infrared absorption spectrum, and physical properties as shown below.
-Naphthyl N-(6-medoxy-2-pyridyl)-N
-Identified as methylthiocarbamate. The yield is 8-
(2,4-dinitrophenyl) was 75.9% relative to N-(6-medoxy 2-pyridyl)-N-methylthiocarbamate and 68.1% relative to the starting material 6-medoxy 2-methylaminopyridine. .

υ elemental analysis value (as CtsHtaN2028) Ol
1N8 analysis value <@ 66.49 4.98 8.58
9.94 theoretical value (9)) 66.67 4.
94 8.64 9.880 Nuclear magnetic resonance absorption spectrum (CDOla, internal standard TM8) δ-ppm δ 3.75 (3H8) δ 3.92 (31f S) δ 6.58-
6.66(11(,d)δ 6.89-7.87 (9
H,m)O infrared absorption spectrum (KBr method) α-1 1610, 1465, 1430, 1880, 1B351
270.1180,1040. 820. 750JU
Molecular weight by C-81S: 3240 Physical properties: Melting point: 95.6° to 96.5°C Solubility: Easily soluble in Hensen, chloroform, and N,N-dimethylformamide.

Soluble in lower alcohols. water, hexa Married to husband.

Examples 2 to 10 Alkyl group of the starting material of general formula (1) used in (step A), strong base, solvent, halogen of the compound of general formula (5) used in (step B), solvent, (step C) The general formula 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 (to) as shown in Table 1 to obtain the corresponding O-aryl N-(6-alkoxy-2-
pyridyl)-N-alkylthiocarbamate was obtained. As in Example 1, they were identified based on elemental analysis values, molecular weights determined by Go-MS, nuclear magnetic resonance absorption spectra, infrared absorption spectra, physical properties, etc. The various data obtained are shown in Table 2.

Table 1 Note (1) Tetrahydrofuran is abbreviated as TrIF.

Note (2) N,N-dimethylformamide is abbreviated as DMF.

(Effects of the Invention) The method of the present invention is useful as an intermediate for pharmaceuticals and agricultural chemicals.
Ryl N-(6-alkoxy-2-pyridyl)-N-
When producing alkylthiocarbamates, 6-6-
The present invention provides a new manufacturing method consisting of a series of steps starting from reacting alkoxy-2-alkylaminopyridine with carbon disulfide. In each step, the reaction proceeds under mild conditions, and the target product with high purity can be obtained in good yield. One sulfur atom in carbon disulfide is recovered as a thiophenol derivative in the final step, which is also useful as an intermediate raw material for medicines and agricultural chemicals (f-).

Applicant fMw Ct, Representative of U Kogyo Co., Ltd. 1) Yuji Procedural Amendment (Voluntary) October 1985” Japan Law 3, Relationship with the case of the person making the amendment Patent applicant 〒675-01 5, Amendment Contents (1) The claims on pages 1 to 4 of the specification are amended as follows.

"O-aryl-N-(6-alkoxy-2
-pyridyl)-N-alkylthiocarnocarnomate, (R1 and R2 are the same alkyl groups as in general formula (1)) 6-alkoxy-2-alkylaminopyridine represented by a strong base (+<i, R2 is the same alkyl group as in the general formula (I), M is an alkali gold IAk). pyridyl)-
Step of producing an alkali metal salt of N-alkyldithiocarbamate; 5-(2,4-dinitrophenyl)N-
Step of producing (6-alkoxy-2-pyridyl)-N-alkyldithiocarbamate,
) is reacted with a phenol represented by the general formula % formula %) (Ar represents an aryl group) in a solvent to form an O-aryl N-( represented by the general formula (I)). A process for producing 0-aryl N-(6-alcokyne-2-pyridyl)-N-furkylthiocarbamate, which comprises the steps of producing 0-aryl N-(6-alcokyne-2-pyridyl)-N-furkylthiocarbamate. Law.

(2) General formula (I), (b), (III),
The method according to claim (1), wherein R1 and R2 of (fV) are both methyl groups.

(3) The method according to claim (1), wherein Ar in general formula (I) is a 2-su7tyl group.

(4) The method according to claim (1), wherein M in general formula (III) is sodium.

(5) The method according to claim (1), wherein X in the general formula (ff) is chlorine.

(6) The method according to claim (1), wherein 11 um to be hydrogenated is used as a strong base during the production of the alkali metal salt represented by general formula (111).

(7) Claim (1) states that N,N-dimethylformamide is used as the enzyme when reacting the dithiocarbamate derivative represented by the general formula (V) with the phenol represented by the general formula (Vl). the method of. ” The following amendments are made.

(3) 12 pages of detailed letter! 13 rows 1 formula (C), (D)
shall be corrected as follows.

(C) (D) Procedural amendment (voluntary) January 30, 1985 Michibe Uga, Commissioner of the Patent Office 1, Indication of case 1985 Patent Application No. 190205 2, Title of invention Production of thiocarbamate derivatives Law 3
, Relationship with one person making an amendment Patent applicant: 675-01 4. Subject of amendment Description 5, @Correct content A The scope of claims is amended as shown in the attached sheet.

B Amend the detailed description of the invention in the book as follows4, ,2,'i:! (1) Examples 11 and 12 are added after Actual Example 10 in Table 1 on page 19 of the Specification 3. (21 The following section is added after Table 1 on page 20 of the Specification.

(3) The following paragraph is added after Table 2 on page 21 of the specification.

Attachment (ELt and FL2 are independent of each other and represent an alkyl group from 01 to C8, and Ar represents an aryl group.) 0-aryl-N-(6-alkoxy-2
-Pyridyl)-N-alkylthiocarbamate is produced by substituent 1 (ELt, a2 represents the same alkyl group as in general formula (I)). Carbon disulfide is reacted in the presence of a strong base, S (al, R2 is the same alkyl group as in general formula (1),
M represents an alkali metal. ) N-(5-alkoxy-2-pyridyl)-
Step of producing an alkali metal salt of N-alkyldithiocarbamate, (1) Next, reacting the alkali metal salt represented by the above formula (1) with 2,4-dinitrohalobenzene represented by the general formula (X represents a halogen atom). 8-(2,4-dinitrophenyl)N-
Step of producing (6-alkoxy-2-pyridyl)-N-alkyldithiocarbamate, (1) then the formula (
Y) is reacted with a phenol represented by the general formula % (Ar represents an aryl group) in a solvent to form an O-aryl N represented by the general formula (1). A method for producing O-aryl N-(6-alkoxy-2-pyridyl)-N-alkylthiocarbamate, comprising the steps of producing -(6-alkoxy-2-pyridyl)-N-alkylthiocarbamate.

(2) General formula (1), (I), (1), (Is'
The method according to claim (1), wherein both Rt and R2 of ) are methyl groups.

+81 The method according to claim (1), wherein Ar in general formula (I) is a 2-naphthyl group.

(5) The method according to claim (1), wherein M in general formula (1) is sodium.

(6) Claims in which X in the general formula (■) is chlorine (
The method described in 1).

(7) The method according to claim (1), wherein sodium hydride is used as a strong base when producing the alkali metal salt represented by general formula (1).

(8) Claim (1) wherein N,N-dimethylformamide is used as a solvent when reacting the dithiocarbamate derivative represented by the general formula (V) with the phenol represented by the general formula (VI). Method. ”

Claims (7)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) R_1 and R_2 are independent of each other and represent an alkyl group of C_1 to C_3, and Ar represents an aryl group. O-aryl-N-(6-alkoxy-2
-pyridyl)-N-alkylthiocarbamate [1] General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (R_1 and R_2 represent alkyl groups similar to general formula (I).) 6-alkoxy-2-alkylaminopyridine represented by the formula (III) is reacted with carbon disulfide in the presence of a strong base, R_1 and R_2 are the same alkyl groups as in the general formula (I), and M is an alkali group. Indicates metal. N-(6-alkoxy-2-pyridyl)-
A process for producing an alkali metal N-alkyldithiocarbamate salt. [2] Next, the alkali metal salt represented by the above formula (III) has the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (X represents a halogen atom) 2,4-dinitrohalobenzene The reaction produces S-(2,4-dinitrophenyl) represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (V) (R_1 and R_2 represent the same alkyl groups as in general formula (1).)
A process for producing N-(6-alkoxy-2-pyridyl)-N-alkyldithiocarbamate. [3] Next, the dithiocarbamate derivative represented by the above formula (V) is reacted with a phenol represented by the general formula Ar-OH (VI) (Ar represents an aryl group) in a solvent to obtain the dithiocarbamate derivative represented by the above general formula. A process for producing the O-aryl N-(6-alkoxy-2-pyridyl)-N-alkylthiocarbamate. A method for producing O-aryl N-(6-alkoxy-2-pyridyl)-N-alkylthiocarbamate, characterized by comprising: (2) R_ of general formulas (I), (II), (III), (IV)
Claims 1 and R_2 are both methyl groups (1
) method described. (3) The method according to claim (1), wherein Ar in general formula (I) is a 2-naphthyl group. (4) The method according to claim (1), wherein M in general formula (III) is sodium. (5) Claims in which X in general formula (IV) is chlorine (
The method described in 1). (6) The method according to claim (1), wherein sodium hydride is used as a strong base when producing the alkali metal salt represented by general formula (III). (7) Claim (1) in which N,N-dimethylformamide is used as a solvent when reacting the dithiocarbamate derivative represented by the general formula (V) with the phenol represented by the general formula (VI). Method.