JPH0586387B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a method for producing 4-carboxy-5-halogenopyrazole derivatives. 4-Carboxy-5-halogenopyrazole derivatives are useful as intermediates for pharmaceuticals, agricultural chemicals, and the like. For example, examples of the use of 4-carboxy-5-halogenopyrazole derivatives as intermediates are described in JP-A-59-122488 and European Patent Publication No. 87780. Prior Art The following methods are conventionally known for obtaining 4-carboxy-5-halogenopyrazole derivatives. That is, a 4-carboxy-5-hydroxypyrazole derivative is halogenated by heating and reacting with phosphorus oxychloride or the like to obtain a 4-carboxy-5-halogenopyrazole derivative.

embedded image [In the formula, A and B each independently represent a hydrogen atom or a lower alkyl group. R represents a lower alkyl group. X represents a chlorine atom or a bromine atom. ] Problems to be solved by the invention described in JP-A-59-122488 Problems with this method include the following. (1) Since a large amount of 4-carboxylic acid pyrazole derived from ester hydrolysis is produced as a by-product, an additional esterification step is required. (2) Since a large amount of phosphorus oxychloride or phosphorus oxybromide is used as a reaction reagent, it is necessary to remove excess phosphorus oxychloride or phosphorus oxybromide after the reaction is completed. Not only is it economically disadvantageous, but it also requires treatment of phosphorus in the waste liquid, which is not necessarily advantageous from an industrial perspective. (3) Requires long and high temperature reaction conditions. Means for Solving the Problems and Aspects of the Invention The present inventors used 5-amino-4-carboxypyrazole as a raw material, and in the presence of hydrochloric acid or hydrobromic acid, nitrite, inorganic nitroso compound, sesquioxide Found a method to obtain the desired 4-carboxy-5-halogenopyrazole derivative by diazotization using a nitrite source selected from nitrogen or nitric oxide, and then decomposition in the presence of sulfur dioxide or sulfite. Ta. The method of the present invention is 5
- a diazotization step of diazotizing the amino-4-carboxypyrazole derivative using a nitrous acid source;
It consists of a decomposition step in which the generated diazonium salt is decomposed in the presence of sulfur dioxide or sulfite to obtain a 4-carboxy-5-halogenopyrazole derivative.

embedded image [In the formula, A and B each independently represent a hydrogen atom or a lower alkyl group. R represents a lower alkyl group. X represents a chlorine atom or a bromine atom. ] The hydrochloric acid or hydrobromic acid used in the diazotization step is
20 molar equivalents are used, preferably 3 to 8 molar equivalents. As a nitrite source used in the diazotization step, nitrites such as sodium nitrite, potassium nitrite, and calcium nitrite can be used, and inorganic nitroso compounds such as nitrosyl sulfate and nitrosyl chloride can be used. As a nitrous acid source, 1 to 2 molar equivalents, preferably 1 to 2 molar equivalents, preferably 1
~1.3 equivalents are used. The reaction in the diazotization step is carried out at a temperature range of -50 to 50°C, preferably -5 to 20°C. Furthermore, if excess nitrous acid remains after the reaction is completed, it can be decomposed and removed with urea or the like. In the decomposition step, the diazonium salt is decomposed in the presence of sulfur dioxide or sulfite as a catalyst.
Generally, a copper-based catalyst such as copper chloride is used as a catalyst for the decomposition of diazonium salts, and the yield is relatively good. In addition, rare cases have been reported in which catalysts based on iron, nickel, manganese, or cobalt are used. The method of the present invention is characterized in that sulfur dioxide or sulfite is used as a catalyst for the decomposition of the diazonium salt. As far as we know, this has not been known until now. The present invention was completed by discovering that when sulfur dioxide or sulfite is used as a catalyst, the desired 4-carboxy-5-halogenopyrazole derivative can be obtained at a higher yield than the commonly used copper-based catalysts. I let it happen. Sulfur dioxide or sulfite used as a catalyst in this decomposition step is 0.1 to 100 wt%, preferably 10 to 100 wt%, based on the raw material aminopyrazole derivative ().
Use 40wt%. The reaction in the decomposition step is -50 to 50°C, preferably -5
Perform at a temperature range of ~30°C. In the decomposition reaction, halogenated alkyl derivatives such as carbon tetrachloride and dichloroethane, benzene derivatives such as benzene, toluene and chlorobenzene, and aliphatic hydrocarbons such as hexane and heptane can also be used as inert solvents. The reaction sequence can be carried out by various methods known for general diazotization reactions and decomposition reactions of diazonium salts. For example, a method in which a prepared solution of diazonium salt is dropped into a reactor containing sulfur dioxide or sulfite and an organic solvent, a method in which sulfur dioxide or sulfite is added to a prepared solution of diazonium salt and decomposed, or amino Pyrazole derivatives (), hydrochloric or hydrobromic acid,
Various order combinations may be used, such as a method in which a nitrous acid source such as sodium nitrite is added to a reactor containing sulfur dioxide or sulfite and an organic solvent, and the diazotization step and the decomposition step are carried out simultaneously. After the reaction, the organic layer is separated, the solvent is distilled off, and the mixture is distilled under normal pressure or reduced pressure to obtain the desired 4-carboxy-5-halogenopyrazole derivative (). Effects of the Invention The following points can be enumerated as advantages of the present invention. (1) Compared to the method of treating the 2-hydroxyl compound () with phosphorus oxyhalide, the desired 4-carboxy-5-halogenopyrazole derivative () can be produced in a short time and in high yield under mild conditions. can get. (2) Since diazonium salts can be decomposed in high yield with sulfur dioxide or sulfite without using copper salts, which are normally used to decompose diazonium salts, there is no risk of contamination of environmentally undesirable heavy metals such as copper into wastewater. Furthermore, there is no fear that phosphorus derived from phosphorus oxyhalide will be mixed into wastewater, which is environmentally preferable. Examples Specific examples of the present invention are shown below, but the present invention is not limited to the following examples unless the gist of the present invention is exceeded. Example 1 Production of ethyl 5-chloro-1-methylpyrazole-4-carboxylate 200 g of ethyl 5-amino-1-methylpyrazole-4-carboxylate was dissolved in 1000 ml of 35% hydrochloric acid.
Cooled to 13°C. Next, 106.3 g of sodium nitrite with a purity of 97% was dissolved in 220 ml of water and added while keeping the temperature below 15°C. Urea after stirring at 10℃ for 10 minutes
20g was added and stirred for an additional 10 minutes. This solution was added dropwise at 5°C to a solution in which 56 g of sulfite was absorbed into 1000 ml of carbon tetrachloride. After stirring at room temperature until no nitrogen gas was generated, 1000 ml of water was added and the organic layer was separated. After adding 500 ml of carbon tetrachloride to the aqueous layer and performing an extraction operation, the organic layer was combined with the previous organic layer, washed with water, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off to obtain crude 5-chloro-1-methylpyrazole- 213.8 g of ethyl 4-carboxylate was obtained. This crude product was distilled to obtain 207.9 g of pure target product. Boiling point: 104-110°C/3 mmHg Yield: 93% Example 2 Production of methyl 5-chloro-1-methylpyrazole-4-carboxylate Synthesis was performed according to Example 1 above. Melting point 70-71°C Example 3 5-chloro-1,3-dimethylpyrazole-4
-Production of ethyl carboxylate Synthesis was performed according to Example 1 above. Boiling point 129℃/5mmHg Melting point 40-42℃ Example 4 Production of ethyl 5-bromo-1-methylpyrazole-4-carboxylate 10g of ethyl 5-amino-1-methylpyrazole-4-carboxylate was dissolved in 50ml of 35% hydrochloric acid. Melt at 13℃
It was cooled to Next, 97% purity sodium nitrite
5.5g was dissolved in 11ml of water and added while keeping the temperature below 15°C. After stirring for 10 minutes at 10°C, 1 g of urea was added, and the mixture was further stirred for 10 minutes. This solution was added dropwise at 5°C to a solution containing 110 ml of 47% hydrobromic acid, 50 ml of carbon tetrachloride, and 2 g of sulfite. After stirring at room temperature until no nitrogen gas was generated, 500 ml of water was added and the organic layer was separated. After washing with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 11.0 g of crude ethyl 5-bromo-1-methylpyrazole-4-carboxylate.
This crude material was distilled to obtain 7.0 g of the target product. Boiling point 120℃/3mmHg Melting point 39-42℃ Yield 50.7% Example 5 Production of ethyl 5-chloro-1-methylpyrazole-4-carboxylate (alternative method) 5-amino-1-methylpyrazole-4-carboxylic acid A diazonium salt solution was prepared according to Example 1 using 10 g of ethyl, and 4 g of sulfite was blown into the solution at 5°C. After no nitrogen gas is generated, stir at room temperature for 1 hour, then add 200 ml of water and 100 ml of chloroform.
was added to perform the extraction operation. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 11.6 g of crude ethyl 5-chloro-1-methylpyrazole-4-carboxylate. This crude product was distilled to obtain 9.9 g of the target product. Boiling point: 104-110°C/3 mmHg Yield: 88% Example 6 Production of ethyl 5-chloro-1-methylpyrazole-4-carboxylate (alternative method) Using 6.3 g of nitrosyl chloride in place of sodium nitrite in Example 1 A diazonium salt solution was prepared according to Example 1 from 10 g of ethyl 5-amino-1-methylpyrazole-4-carboxylate. This diazonium salt solution was decomposed according to Example 5,
9.6g of the target product was obtained. Boiling point 104-110℃/3mmHg Yield 86.1% Next, 5-amino-1 was added to the raw material according to Example 1.
-ethyl pyrazole-4-carboxylate 10g
5-chlor-
The results of obtaining ethyl 1-methylpyrazole-4-carboxylate are shown below as Examples 7 to 13 together with reference examples.

【table】 The by-product has the following structural formula.

【formula】

Claims (1)

[Claims] 1 General formula () [Formula] [In the formula, A and B each independently represent a hydrogen atom or a lower alkyl group. R represents a lower alkyl group. ] The aminopyrazole derivative represented by is diazotized using a nitrite source selected from nitrite, an inorganic nitrone compound, nitrogen sesquioxide, or nitrogen monoxide in the presence of hydrochloric acid or hydrobromic acid, and then diazotized with a nitrite source selected from nitrite, an inorganic nitrone compound, nitrogen sesquioxide, or nitrogen monoxide. The following formula () is characterized in that it is decomposed in the presence of sulfur or sulfite. [Formula] [In the formula, A and B each independently represent a hydrogen atom or a lower alkyl group. R represents a lower alkyl group. X represents a chlorine atom or a bromine atom. ] A method for producing a 4-carboxy-5-halogenopyrazole derivative represented by: