JP3006091B2 - Method for producing substituted pyrazole - 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 a substituted pyrazole, and in particular, 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]

2. Description of the Related Art Conventionally, the following method is known as a method for producing a substituted pyrazole by reacting an acylpyruvate with an alkylhydrazine.

[0003] Ethyl acetylpyruvate is reacted with methylhydrazine in aqueous solution at 80 ° C to give the dimethyl-ethoxycarbonylpyrazole isomer, ie
1,3-dimethyl-5-ethoxycarbonylpyrazole (hereinafter referred to as "pyrazole (I)") and 1,5-dimethyl-3-ethoxycarbonylpyrazole (hereinafter referred to as "pyrazole (II)") are pyrazole ( I): Method for obtaining pyrazole (II) = 25: 75 composition (Bull. Soc. Che
m. France 1966, 293).

A method in which ethyl acetylpyruvate is dissolved in ethanol and treated with methylhydrazine to similarly obtain an isomer mixture of pyrazole (I): pyrazole (II) = 58: 42 (JP-A-52-87168) Gazette).

[0005] Ethyl 3-trifluoromethylbenzoylpyruvate in ethanol at a reaction temperature of 80
C. react with methylhydrazine to give 1-methyl-3-
(3-trifluoromethylbenzoyl) -5-ethoxycarbonylpyrazole: 1-methyl-3-ethoxycarbonyl-5- (3-trifluoromethylbenzoyl)-
A method of obtaining an isomer mixture having a composition of pyrazole = 75: 25 (JP-A-59-95272).

[0006]

Thus, 1-alkyl-3-alkyl (or aryl) -substituted-5-alkoxycarbonylpyrazole is synthesized by reacting an acylpyruvate with an alkylhydrazine by a known method. In this case, the selectivity to the target isomer is 25 to 75.
%, Which is formed as a mixture with other regioisomers. For this reason, the product substituted pyrazole is used for pesticides,
When used as a pharmaceutical intermediate, separation operations such as purification, distillation or fractional recrystallization are indispensable, and it is difficult to control the production ratio between isomers, so that the yield is directly reduced. This is a major problem for practical use.

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

[0008]

The process for producing a substituted pyrazole according to the present invention comprises reacting an acylpyruvate with an alkylhydrazine to form a 1-alkyl-3-alkyl (or aryl) -substituted-5-alkoxycarbonylpyrazole. In the production, one or more solvents selected from the group consisting of amides, alcohols, ethers, aromatic hydrocarbons and amines are used, and the molar ratio of alkylhydrazine to acylpyruvate in the solvent is 1 or more. It is characterized by reacting under large conditions.

Hereinafter, the present invention will be described in detail. In the present invention, the acylpyruvate used as a raw material is an alkyl ester of an acyl-substituted product such as acetyl, propionyl, butyryl, and benzoyl of pyruvate, wherein the ester is methyl, ethyl, propyl,
Those which are esters such as butyl or benzyl are preferred.

[0010] Other raw materials such as alkylhydrazine include monomethylhydrazine, monoethylhydrazine, mono-n-propylhydrazine, mono-iso-propylhydrazine, mono-t-butylhydrazine, mono-n-hydrazine.
Butylhydrazine, phenylhydrazine and the like are preferred.

In the method of the present invention, the reaction temperature is not particularly limited. However, when the reaction temperature is 40 ° C. or higher, the selectivity of the target isomer is reduced, and a purity of the target isomer of 80 mol% or more can be obtained. Although the reaction proceeds even when the reaction temperature is −10 ° C. or lower, it is difficult to carry out the reaction practically because of the efficiency of the reaction heat removal. In particular, it is preferable to carry out in the range of 0 ° C to 30 ° C.

The solvent used in the method of the present invention must dissolve both the starting acylpyruvate and the alkylhydrazine and must have high selectivity in the reaction. In the present invention, examples of such a solvent 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 are used. 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 is in the range of 5 to 30% by weight of the solvent, but it is also possible to use them outside of this range.

In the method of the present invention, when the acylpyruvate is reacted with the alkylhydrazine, the reaction is carried out under the condition that the molar ratio of the alkylhydrazine to the acylpyruvate in the solvent is always greater than 1. When the molar ratio in the solvent is less than 1, 1-alkyl-3
The selectivity to the -alkyl (or aryl) -substituted-5-alkoxycarbonylpyrazole decreases, and the result of the isomer selectivity of 80 mol% or more as in the method of the present invention cannot be obtained.

The method of the present invention can be carried out by either a batch operation or a flow operation. In the case of batch operation, an alkylhydrazine, preferably an aqueous solution of alkylhydrazine is dissolved in the solvent specified in the present invention, and the reaction is carried out by adding a predetermined amount of an acylpyruvate. In the case of a flow-type operation, it can be carried out by making the molar ratio of alkylhydrazine to acylpyruvate greater than 1 and instantly mixing both.

[0016]

When the process of the present invention is carried out under preferable conditions, the reaction between the alkyl hydrazine and the acyl pyruvate proceeds in two steps. That is, in the first step, an intermolecularly dehydrated hydrazone is formed from the alkyl hydrazine and the acylpyruvate, and then in the second step, the hydrazone is further dehydrated and ring-closed in the molecule to form the desired 1-alkyl-3-. Alkyl (or aryl) substituted-5-alkoxycarbonylpyrazoles are selectively produced. By the way, under the reaction conditions other than the method of the present invention, since the whole system is neutral or acidic due to the starting diketone or the solvent itself, the two-stage reaction cannot be distinguished and directly produces the final substituted pyrazole. For this reason, the selectivity for the production of 1-alkyl-3-alkyl (or aryl) -substituted-5-alkoxycarbonylpyrazoles is low.

[0017]

The present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to the following examples unless it exceeds the gist.

Example 1 A mixture obtained by dissolving 4.89 g of a 47% by weight aqueous solution of monomethylhydrazine (0.05 mol as monomethylhydrazine (hereinafter abbreviated as "MMH")) in 18 g of ethanol was stirred and cooled with ice. Below, 8.44 g of ethyl propionylpyruvate (0.049 mol as propionylpyruvate ethyl ester (hereinafter abbreviated as “PPE”) having a purity of 97% by weight was gradually added dropwise. One and a half hours were required for dropping, and during that time, the temperature of the mixture was kept at 10 ° C. or lower. After completion of the dropwise addition, the mixture was left for 30 minutes, and 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 formation ratio of -ethyl-pyrazole (hereinafter, referred to as "pyrazole [B])" is 87.3: 12.7.
Met.

Examples 2 to 4 In Example 1, the type and amount of the solvent,
The same operation as in Example 1 was performed except that the reaction ratio between H and PPE was set to the value shown in Table 1. Table 1 also shows the results of the GC analysis.

[0020]

[Table 1]

Example 5 5.53 g (0.12 g) of monomethylhydrazine (MMH)
mol) was dissolved in 50 g of toluene while stirring, while cooling with ice, ethyl acetate acetylpyruvate (98% by weight) (hereinafter abbreviated as “APE”) 15.81.
g (0.1 mol) was gradually added dropwise. One and a half hours were required for dropping, and the temperature of the mixture was kept at 10 ° C. or lower during that time.
After the completion of the dropwise addition, the mixture was further allowed to stand for 30 minutes and then analyzed by GC. As a result, the reaction yield was 95.0 mol%, and 1,3-dimethyl-5-ethoxycarbonylpyrazole (hereinafter, referred to as "pyrazole [C]"). And 1,5-dimethyl-3
The formation ratio of -ethoxycarbonylpyrazole (hereinafter, referred to as "pyrazole [D])" was 91.4: 8.6.

Example 6 The procedure of Example 5 was repeated, except that diisopropyl ether was used instead of toluene as the solvent. Table 2 also shows the results of the GC analysis.

[0023]

[Table 2]

COMPARATIVE EXAMPLE 1 8.85 g (0.05 mol) of ethyl propionylpyruvate (PPE) having a purity of 97% by weight was dissolved in 9.3 g of methanol, and a 47% by weight aqueous solution of monomethylhydrazine (MMH) 4 was rapidly stirred. .89 g (0.05 mol as MMH) was gradually added dropwise. Reaction temperature 10 ° C
It took one hour to drop. After completion of the dropwise addition, the mixture was kept at 10 ° C. for 30 minutes, and the reaction mixture was analyzed by GC. As a result, a result of 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 the solvent,
Except that the reaction ratio between H and PPE was the value shown in Table 3,
The same operation was performed as in Comparative Example 1. Table 3 shows the results of GC analysis.
Shown in

[0026]

[Table 3]

[0027]

As described in detail above, according to the method for producing a substituted pyrazole of the present invention, a 1-alkyl-3-alkyl (or aryl) -substituted-5-alkoxycarbonylpyrazole useful as an intermediate for medicines and agricultural chemicals. Can be easily obtained with high selectivity and high yield.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Kenji Yoshida 1000 Kamoshita-cho, Midori-ku, Yokohama-shi, Kanagawa Prefecture Inside Mitsubishi Chemical Research Laboratory (56) References JP-A-2-292263 (JP, A) JP-A Heisei 1-283274 (JP, A) JP-A-1-168675 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 231/14-231/52 CA (STN) REGISTRY (STN) )

Claims (1)

(57) [Claims] 1. An amide, an alcohol, an ether, an aromatic hydrocarbon for producing a 1-alkyl-3-alkyl (or aryl) -substituted-5-alkoxycarbonylpyrazole by reacting an acylpyruvate with an alkylhydrazine. And at least one solvent selected from the group consisting of amines and amines, wherein the reaction is carried out under the condition that the molar ratio of alkylhydrazine to acylpyruvate in the solvent is greater than 1. Method.