JPH04224565A - Production of substituted pyrazole - Google Patents

Abstract

PURPOSE:To readily obtain an 1-alkyl-3-alkyl(or aryl)-substituted-5- alkoxycarbonylpyrazole useful as an intermediate for medicine and agricultural chemical in high selectivity. CONSTITUTION:An 1-alkyl-3-alkyl(or aryl)-substituted-5-alkoxycarbonylpyrazole is produced by reacting an acylpyruvic acid ester with an alkylhydrazine. The above-mentioned reaction is carried out using a solvent selected from an amide, alcohol, ether, aromatic hydrocarbon and amine in condition having a molar ratio of the alkylhydrazine to acylpyruvic acid ester in the solvent being larger than 1.

Description

[Detailed description of the invention]

0001

[Field of Industrial Application] The present invention relates to a method for producing substituted pyrazoles, particularly 1, which is useful as an intermediate for pharmaceuticals and agricultural chemicals.
-alkyl-3-alkyl (or aryl) substituted-5-
The present invention relates to a method for producing alkoxycarbonylpyrazole with high selectivity.

0002

BACKGROUND OF THE INVENTION Conventionally, the following methods are known as methods for producing substituted pyrazoles by reacting acylpyruvate esters with alkylhydrazines.

■ Reacting acetylpyruvate ethyl ester with methylhydrazine in an aqueous solution at 80°C,
Dimethyl-ethoxycarbonylpyrazole isomers, namely 1,3-dimethyl-5-ethoxycarbonylpyrazole (hereinafter referred to as "pyrazole (I)") and 1,5
-Dimethyl-3-ethoxycarbonylpyrazole (hereinafter referred to as "pyrazole (II)") is converted to pyrazole (I
): Method for obtaining pyrazole (II) with a composition of 25:75 (Bull. Soc. Chem. France
1966, 293).

■ Acetylpyruvic acid ethyl ester is dissolved in ethanol and treated with methylhydrazine.
Similarly, pyrazole (I): pyrazole (II) = 58:
Method for obtaining 42 isomer mixtures (JP-A-52-8716
Publication No. 8).

■ 3-Trifluoromethylbenzoylpyruvate ethyl ester in ethanol at a reaction temperature of 8
Reacted with methylhydrazine at 0°C to form 1-methyl-3
-(3-trifluoromethylbenzoyl)-5-ethoxycarbonylpyrazole: 1-methyl-3-ethoxycarbonyl-5-(3-trifluoromethylbenzoyl)
- A method for obtaining an isomer mixture having a composition of pyrazole = 75:25 (JP-A-59-95272).

[0006]

[Problems to be Solved by the Invention] As described above, 1-alkyl-3-alkyl (or aryl) substituted-5-alkoxycarbonylpyrazole is synthesized by reacting an acylpyruvate ester with an alkylhydrazine by a known method. In this case, the selectivity to the target isomer is 25 to 75
%, which is produced as a mixture with other positional isomers. For this reason, the product substituted pyrazole can be used as a pesticide,
When used as a pharmaceutical intermediate, separation operations such as purification, distillation, or fractional recrystallization are essential, and since it is difficult to control the production ratio between isomers, there is a direct decrease in yield. This leads to a major problem in practical application.

The present invention solves the above-mentioned conventional problems, and in a method for producing a substituted pyrazole by reacting an acylpyruvate ester with an alkylhydrazine, one of the isomers of the substituted pyrazole produced, Specifically, 1-alkyl-3-alkyl (or aryl) substitution-
5-alkoxycarbonylpyrazole with isomer selectivity of 8
The purpose is to provide an efficient manufacturing method with a selectivity of 0 mol% or more.

[0008]

[Means for Solving the Problems] The method for producing a substituted pyrazole of the present invention comprises reacting an acylpyruvic acid ester with an alkylhydrazine to obtain a 1-alkyl-3-alkyl (1-alkyl-3-alkyl
or aryl) substituted-5-alkoxycarbonyl pyrazole, using one or more solvents selected from the group consisting of amides, alcohols, ethers, aromatic hydrocarbons, and amines, The reaction is characterized in that the molar ratio of alkylhydrazine to acid ester is greater than 1.

The present invention will be explained in detail below. In the present invention, the acyl pyruvate ester used as a raw material is an alkyl ester of an acyl substituted product of pyruvate such as acetyl, propionyl, butyryl, benzoyl, etc., and the ester is methyl, ethyl, propyl,
Esters such as butyl or benzyl are preferred.

Other raw material alkylhydrazines include monomethylhydrazine, monoethylhydrazine, mono-n-propylhydrazine, mono-iso-propylhydrazine, mono-t-butylhydrazine, mono-n-
Preferred examples include butylhydrazine and phenylhydrazine.

[0011] In the method of the present invention, the reaction temperature is not particularly limited, but if the reaction temperature is 40°C or higher, the selectivity of the target isomer decreases, and it is difficult to obtain the target isomer purity of 80 mol% or higher. Although the reaction proceeds even when the reaction temperature is -10°C or lower, it is difficult to carry out in practice due to the efficiency of reaction heat removal. In particular, it is preferable to conduct the reaction at a temperature in the range of 0°C to 30°C.

The solvent used in the method of the present invention must be capable of dissolving both the starting acylpyruvate ester and the alkylhydrazine and must have high selectivity in the reaction. In the present invention, such solvents include amide solvents such as dimethylformamide and dimethylacetamide, alcohol solvents such as methanol, ethanol, propanol and butanol, and ether solvents such as diisopropyl ether, di-n-butyl ether and tetrahydrofuran. , aromatic hydrocarbon solvents such as benzene, toluene and xylene, and amine solvents such as pyridine, picoline and trialkylamine. These solvents may be used alone or as a mixed solvent of two or more.

The amount of these solvents used is preferably such that the product accounts for 5 to 30% by weight of the solvent, but it is also possible to use them outside this range.

In the method of the present invention, when acylpyruvate and alkylhydrazine are reacted, the reaction is carried out under conditions such that the molar ratio of alkylhydrazine to acylpyruvate in the solvent is always greater than 1. If the molar ratio in this solvent is less than 1, 1-alkyl-3
The selectivity to -alkyl (or aryl)-substituted -5-alkoxycarbonylpyrazole decreases, making it impossible to obtain an isomer selectivity of 80 mol% or more as in the method of the present invention.

The method of the present invention can be carried out in either batch or flow-through operation. In the case of batch operation, an alkylhydrazine, preferably an aqueous alkylhydrazine solution, is dissolved in the solvent specified in the invention and reacted by adding a predetermined amount of acylpyruvate. In addition, in the case of flow-through operation, the molar ratio of alkylhydrazine to acylpyruvate ester is set to 1.
This can be carried out by making the mixture larger and instantly mixing the two.

[0016]

[Operation] When the process of the present invention is carried out under preferred conditions, the reaction between the alkylhydrazine and the acylpyruvate ester proceeds in two stages. That is, in the first step, hydrazone is generated by intermolecular dehydration from alkylhydrazine and acylpyruvate, and then in the second step, hydrazone is further dehydrated and ring-closed within the molecule to form the target product, 1-alkyl-3- Alkyl (or aryl) substituted-5-alkoxycarbonylpyrazoles are selectively produced. Incidentally, under reaction conditions other than the method of the present invention, the entire system is neutral or acidic due to the starting diketone or the solvent itself, so the two-step reaction cannot be distinguished, and the final substituted pyrazole is directly produced. Therefore, the selectivity for producing 1-alkyl-3-alkyl (or aryl)-substituted-5-alkoxycarbonylpyrazole becomes small.

[0017]

[Examples] The present invention will be explained in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

Example 1 A mixture obtained by dissolving 4.89 g of a 47% by weight aqueous monomethyl hydrazine solution (0.05 mol as monomethyl hydrazine (hereinafter referred to as "MMH")) in 18 g of ethanol was cooled on ice while stirring. Then, 8.44 g of propionylpyruvate ethyl ester (0.049 mol as propionylpyruvate ethyl ester (hereinafter abbreviated as "PPE")) having a purity of 97% by weight was gradually added dropwise. The dropwise addition took one and a half hours, during which time the temperature of the mixed solution was maintained at 10° C. or lower. After the dropwise addition was completed, the mixture was left to stand for an additional 30 minutes, and then analyzed by gas chromatography (GC). As a result, the reaction yield was 96.2 mol%, and 1-methyl-3-ethyl-5-ethoxycarbonylpyrazole (hereinafter referred to as "pyrazole [A]") and 1-methyl-3-ethoxycarbonyl-5 The production ratio of -ethyl-pyrazole (hereinafter referred to as "pyrazole [B]") was 87.3:12.7.

Examples 2 to 4 In Example 1, the type and amount of solvent used, and MM
The same procedure as in Example 1 was conducted except that the reaction ratio of H and PPE was set to the value shown in Table 1. The GC analysis results are also shown in Table 1.

[0020]

[Table 1]

Example 5 Monomethylhydrazine (MMH) 5.53g (0.12g
While stirring a mixture obtained by dissolving mol) in 50 g of toluene, under ice cooling, acetylpyruvic acid ethyl ester (hereinafter abbreviated as "APE") 15.81 with a purity of 98% by weight was prepared.
g (0.1 mol) was gradually added dropwise. The dropwise addition took one and a half hours, during which time the temperature of the mixed solution was maintained at 10° C. or lower. After completion of the dropwise addition, after being left for another 30 minutes, GC analysis revealed that the reaction yield was 95.0 mol%, and the reaction yield was 1,3-dimethyl-5-ethoxycarbonylpyrazole (hereinafter referred to as "pyrazole [C]"). and 1,5-dimethyl-3-
Ethoxycarbonylpyrazole (hereinafter referred to as “pyrazole [D
]”. ) production ratio was 91.4:8.6.

Example 6 The same procedure as in Example 5 was carried out except that diisopropyl ether was used instead of toluene as the solvent. The GC analysis results are also shown in Table 2.

[0023]

[Table 2]

Comparative Example 1 8.85 g (0.05 mol) of propionylpyruvate ethyl ester (PPE) with a purity of 97% by weight was dissolved in 9.3 g of methanol, and a 47% by weight monomethylhydrazine (MMH) aqueous solution 4 was dissolved under rapid stirring. .89 g (0.05 mol as MMH) was gradually added dropwise. Reaction temperature 10℃
It took 1 hour for dropping. After the dropwise addition was completed, the reaction mixture was maintained at 10° C. for 30 minutes and analyzed by GC, and a reaction yield of 90 mol% was obtained. The isomer composition was as shown in Table 3.

Comparative Examples 2 to 4 In Comparative Example 1, the type and amount of solvent used, and MM
Except that the reaction ratio of H and PPE was set to the values shown in Table 3,
It was operated in the same manner as in Comparative Example 1. Table 3 shows the GC analysis results.
Shown below.

[0026]

[Table 3]

[0027]

Effects of the Invention As detailed above, according to the method for producing substituted pyrazoles of the present invention, 1-alkyl-3-alkyl (or aryl) substituted-5-alkoxycarbonylpyrazoles useful as intermediates for pharmaceuticals and agricultural chemicals can be produced. can be easily obtained with high selectivity and high yield.

Claims (1)

[Claims] Claim 1: In producing a 1-alkyl-3-alkyl (or aryl) substituted-5-alkoxycarbonyl pyrazole by reacting an acyl pyruvate ester with an alkyl hydrazine, an amide, an alcohol, an ether, an aromatic hydrocarbon, etc. and amines, and the reaction is carried out under conditions in which the molar ratio of alkylhydrazine to acylpyruvate ester in the solvent is greater than 1. Method.