JP3470356B2 - Method for producing mercaptopyrazoles - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing mercaptopyrazoles which are useful as intermediates for medicines and agricultural chemicals. Particularly, the present invention relates to 5-mercaptopyrazole-4-carboxylic acid which is useful as an intermediate for paddy rice herbicides (described in JP-A-59-122488) and corn herbicides (described in JP-A-60-208977). It is effective as a method for producing acid ethyl ester and 3-chloro-5-mercaptopyrazole-4-carboxylic acid methyl ester.

[0002]

2. Description of the Related Art As a method for producing 5-mercaptopyrazoles from 5-halogenopyrazoles, Liebigs Annalen del Semi (Liebigs Annalen
der Chemie), 338, p. 183 (1905),
There is an example of production using an excess amount of sodium sulfide in ethanol. Further, in Japanese Patent Application Laid-Open No. 62-4272, N,
There is an example of using sodium hydrosulfide in N-dimethylformamide.

[0003]

In the method of using sodium sulfide as a sulfiding agent, the reaction proceeds in an equivalent amount to a slight excess amount with respect to the raw material, but since sodium sulfide is strongly alkaline, the raw material is hydrolyzed with an ester or the like. When it has a substituent that is susceptible to decomposition, it causes a decrease in yield. On the other hand, in the method of using sodium hydrosulfide as the sulfiding agent, there is no fear of hydrolysis as described above, but since sodium hydrosulfide is required in an amount of 2 equivalents or more relative to the raw material, it is economically disadvantageous. There are problems such as the treatment of the generated hydrogen sulfide.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for obtaining 5-mercaptopyrazoles in good yield, and as a result, completed the present invention. That is, the present invention relates to a method for producing 5-mercaptopyrazoles from 5-halogenopyrazoles with a sulfiding agent, wherein a carbonic acid compound is allowed to coexist (hereinafter referred to as the method of the present invention). is there.

Examples of 5-halogenopyrazoles include compounds of the formula (1)

[0006]

[Chemical 2]

[In the formula, R ¹ is a hydrogen atom or a carbon atom number 1 to
An alkyl group having 6 carbon atoms, a cycloalkyl group having 1 to 7 carbon atoms, a phenyl group which may have a substituent or an aromatic heterocycle which may have a substituent, R ² represents a hydrogen atom, Alkyl groups having 1 to 6 carbon atoms, 1 to 6 carbon atoms
Represents an alkoxy group, an alkoxycarbonyl group having 1 to 6 carbon atoms, a halogen atom, a cyano group, a phenyl group which may have a substituent or an aromatic heterocycle which may have a substituent, R ³ represents an alkoxycarbonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a nitro group, a halogen atom or a cyano group, X
Represents a halogen atom. ] Is given.

More specifically, in the formula (1), R ¹ represents a methyl group, R ² represents a hydrogen atom or a chlorine atom, and R
³ represents a methoxycarbonyl group or ethoxycarbonyl group, X is 5-halogeno-pyrazoles which represents a chlorine atom. Examples of the sulfiding agent include sodium sulfide and sodium hydrosulfide. The amount of the sulfurizing agent used is usually 1.0 to 1.6 times the molar amount of the halogenopyrazoles,
It is preferably 1.0 to 1.2 times by mole.

Examples of the carbonate compound include carbonate and carbonic acid. Examples of the carbonate include alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate and alkaline earth metal bicarbonate. . Specific examples include sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium hydrogen carbonate, calcium carbonate, barium hydrogen carbonate, barium carbonate, solid or gaseous carbon dioxide, and aqueous solutions thereof. Is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, or solid or gaseous carbon dioxide.

The amount of the carbonic acid compound used is usually 0.1 to 2.0 mol times, preferably 0.2 to 1.1 mol times, relative to the halogenopyrazoles. The solvent used is not particularly limited as long as it is inert to the reaction, for example,
Examples thereof include polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone and pyridine, alcohols such as methanol and ethanol, water and the like.

The reaction temperature is usually 0 to 200 ° C, preferably 10 to 100 ° C. Especially after reacting at low temperature first,
Good results are obtained when the reaction is carried out at a higher temperature. The reaction time is usually 0.1 to 100 hours, preferably 1 to 10 hours. When the reaction temperature cannot be raised due to the boiling point of the solvent, or in order to prevent escape of hydrogen sulfide and carbon dioxide gas generated during the reaction, the reaction can be carried out under pressure in the autoclave.

The method of the present invention focuses on the reactivity of sodium sulfide, sodium hydrosulfide and hydrogen sulfide produced during the reaction, and makes effective use of the sulfiding agent by allowing a carbonic acid compound to coexist. When sodium sulfide is used as the sulfiding agent, sodium hydrosulfide is produced from sodium sulfide by coexisting with a carbonate compound. The reactivity of the sulfurization reaction is higher with sodium hydrosulfide than with sodium sulfide, and because sodium hydrosulfide has a higher solubility in a solvent, sodium hydrosulfide reacts with 5-halogenopyrazoles, and hydrogen sulfide produced as a by-product is Reacts with sodium sulfide to regenerate sodium hydrosulfide. Therefore,
Because sodium hydrosulfide is used as the actual reactant,
It is possible to suppress side reactions such as hydrolysis, and it is possible to recycle the by-produced hydrogen sulfide, which is a problem when using sodium hydrosulfide as a reactant.

On the other hand, when sodium hydrosulfide is used as the sulfiding agent, coexistence of a carbonate can regenerate sodium hydrosulfide from hydrogen sulfide by-produced by reacting with 5-halogenopyrazoles. As a result, sodium hydrosulfide can be effectively used.

[0014]

According to the method of the present invention, the amount of the sulfurizing agent used can be reduced, by-products and side reactions can be suppressed, and 5-mercapto can be easily obtained from 5-halogenopyrazoles in high yield. Pyrazoles can be obtained.

[0015]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Example 1 20.9 g (0.10) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid methyl ester
Mol) was dissolved in 62.7 g of N, N-dimethylformamide, and 14.3 g of 60% sodium sulfide was stirred at room temperature.
(0.11 mol) and anhydrous potassium carbonate 8.3 g
(0.06 mol) was added, and the mixture was reacted at 40 ° C. for 3 hours and then at 70 ° C. for 3 hours. After the reaction,
N, N-dimethylformamide was distilled off, and water was added to dissolve it. When 35% hydrochloric acid was added, white crystals were precipitated,
This was dissolved and extracted with 1,2-dichloroethane. This 1,2-dichloroethane layer was analyzed by internal standard by HPLC to give 20.6 g (yield 99.8%) of 3-chloro-5-
Mercapto-1-methylpyrazole-4-carboxylic acid methyl ester was confirmed.

Example 2 3,5-Dichloro-1-methylpyrazole-4-carboxylic acid methyl ester 20.9
g (0.10 mol) of N, N-dimethylformamide 6
Dissolve in 2.7 g, 60% sodium sulfide with stirring at room temperature 1
4.3 g (0.11 mol) and carbon dioxide (solid) of 0.
After 9 g (0.02 mol) was added and the mixture was reacted at 40 ° C. for 3 hours, it was further reacted at 70 ° C. for 3 hours. After the reaction,
After the same post-treatment as in Example 1, 20.2 g (yield 98.0%) of 3-chloro- was determined by internal standard analysis by HPLC.
5-Mercapto-1-methylpyrazole-4-carboxylic acid methyl ester was confirmed.

Example 3 3,5-Dichloro-1-methylpyrazole-4-carboxylic acid methyl ester 20.9
g (0.10 mol) of N, N-dimethylformamide 6
Dissolve in 2.7 g and stir at room temperature with 60% sodium sulfide 1
4.3 g (0.11 mol), anhydrous potassium carbonate 2.8 g
(0.02 mol) and carbon dioxide (gas) 0.9 g
(0.02 mol) was added, and the mixture was reacted at 40 ° C. for 3 hours and then at 70 ° C. for 3 hours. After completion of the reaction, the same post-treatment as in Example 1 was performed, and 20.3 g (yield 98.5%) of 3-chloro-5 was obtained by internal standard analysis by HPLC.
-Mercapto-1-methylpyrazole-4-carboxylic acid methyl ester was confirmed.

Example 4 5-Chloro-1-methylpyrazole-4-carboxylic acid ethyl ester 18.9 g
(0.10 mol) of N, N-dimethylformamide 95
g, and stirred at room temperature with 70% sodium hydrosulfide 9.6.
g (0.12 mol) and anhydrous potassium carbonate 16.6 g
(0.12 mol) was added and reacted at 95 ° C. for 8 hours. After completion of the reaction, the same post-treatment as in Example 1 was carried out, and HP
By internal standard analysis by LC, 18.0 g (yield 96.8
%) 5-mercapto-1-methylpyrazole-4-carboxylic acid ethyl ester was confirmed.

Example 5 5-chloro-1-methylpyrazole-4-carboxylic acid ethyl ester 18.9 g
(0.10 mol) of N, N-dimethylformamide 95
g, and 70% sodium hydrosulfide under stirring at room temperature 9.
6 g (0.12 mol) and anhydrous sodium carbonate 12.
7 g (0.12 mol) was added and reacted at 95 ° C. for 9 hours. After completion of the reaction, the same post-treatment as in Example 1 was carried out, and H
By internal standard analysis by PLC, 18.1 g (yield 97.0
%) 5-mercapto-1-methylpyrazole-4-carboxylic acid ethyl ester was confirmed.

[Reference Example] 5-chloro-1-methylpyrazole-4-carboxylic acid ethyl ester 18.9 g (0.
10 mol) was dissolved in 95 g of N, N-dimethylformamide and stirred at room temperature with 60% sodium sulfide 14.3 g.
(0.11 mol) was added, and the mixture was reacted at 65 ° C. for 3 hours and then at 90 ° C. for 3 hours. After completion of the reaction, after the same post-treatment as in Example 1, 15.9 g (yield: 85.7%) of 5-mercapto-1-methylpyrazole-4-carboxylic acid ethyl ester was confirmed by internal standard analysis by HPLC. did. At this time, 13% of 5-mercapto-1-methylpyrazole-4-carboxylic acid as a hydrolyzate was by-produced.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 231/18 C07B 61/00 300

Claims (12)

(57) [Claims] 1. A method for producing 5-mercaptopyrazoles from 5-halogenopyrazoles with a sulfurizing agent,
A method comprising coexisting a carbonic acid compound. 2. A 5-halogenopyrazole is represented by the formula (1): [In the formula, R ¹ has a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 1 to 7 carbon atoms, a phenyl group which may have a substituent or a substituent Represents an aromatic heterocycle, R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a halogen atom, cyano. Group, a phenyl group which may have a substituent or an aromatic heterocycle which may have a substituent, R ³ is an alkoxycarbonyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms. Represents an alkylsulfonyl group, a nitro group, a halogen atom or a cyano group, and X represents a halogen atom. ] The method of Claim 1 represented by these. 3. The method according to claim ² , wherein R ¹ represents a methyl group, R ² represents a hydrogen atom or a chlorine atom, R ³ represents a methoxycarbonyl group or an ethoxycarbonyl group, and X represents a chlorine atom. 4. The method according to claim 1, wherein the sulfiding agent is sodium sulfide or sodium hydrosulfide. 5. The sulfurizing agent is sodium sulfide.
The method described. 6. The method of claim 1 wherein the sulfiding agent is sodium hydrosulfide. 7. The method according to claim 1, wherein the carbonic acid compound is a carbonate or carbonic acid. 8. The method of claim 7, wherein the carbonate is an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, an alkaline earth metal bicarbonate or carbonic acid. 9. The method according to claim 7, wherein the carbonate is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium hydrogen carbonate, calcium carbonate, barium hydrogen carbonate, barium carbonate, solid or gaseous carbon dioxide. Method. 10. The method according to claim 7, wherein the carbonate is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or carbon dioxide in solid or gaseous form. 11. The method according to claim 1, wherein the sulfiding agent is sodium sulfide and the carbonic acid compound is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or solid or gaseous carbon dioxide. 12. The method according to claim 1, wherein the sulfiding agent is sodium hydrosulfide and the carbonic acid compound is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate or potassium carbonate.