JP2002220375A - Method for producing pyrazole-5-carboxamides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing pyrazole-5-carboxamides of high purity in a good yield as a compound which is useful for an effective component of medicines and agricultural chemicals, especially insecticides and acaricides. SOLUTION: This method for producing pyrazole-5-carboxamides is characterized by using benzylamines of more than an equimolar quantity based on a total molar quantity of 5-pyrazole carbonylhalides (I) and their equivalent derivative in a reacting material when pyrazole-5-carboxamides represented by the general formula (III) is produced by reacting 5-pyrazole carbonylhalaide represented by the formula (I) with benzlamines represented by the formula (II) in the presence of organic solvent and alkaline aqueious solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing pyrazole-5-carboxamides. More specifically, the present invention relates to a method for producing pyrazole-5-carboxamides, which are compounds useful as active ingredients such as pharmaceuticals and agricultural chemicals, particularly insecticides and acaricides, in high yield and high quality.

[0002]

2. Description of the Related Art As a method for producing pyrazole-5-carboxamides, 5-pyrazolecarbonyl halides and benzylamines are dehydrohalogenated with an organic tertiary base such as triethylamine in a non-aqueous organic solvent. A method of reacting as an agent (JP-A-64-25763),
A method of reacting 5-pyrazolecarbonyl halides with benzylamines in the presence of an aromatic hydrocarbon and an aqueous alkali solution (Japanese Patent Application Laid-Open No. 2-49771) is known.

[0003]

This reaction is an amidation reaction between carbonyl halides and benzylamines, and the molar ratio of both raw materials is 1: 1 as a theoretical amount. JP-A-2-49771 discloses that the charged molar ratio of carbonyl halides to benzylamines is 0.9 to 1.
5: 1 (benzylamines: carbonyl halides =
0.67 to 1.11: 1). However, studies by the present inventors have revealed that the carboxamide obtained may have low purity depending on the reaction conditions. In this case, it is necessary to carry out a purification step such as crystallization, and loss due to the purification operation of the target substance also occurs. Therefore, development of an industrial method capable of obtaining carboxamides with high yield and high quality without purification loss has been desired.

[0004]

The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the fact that the benzylamines become insufficient at the end of the reaction leads to the above-mentioned inconvenience. By using the molar amount of benzylamines in excess of the molar amount of carbonyl halides, high-purity carboxamides can be obtained, and high-quality carboxamides can be obtained only by post-treatment with acid and water. From this, it was found that a high yield could be achieved without purification loss, and the present invention was reached.

That is, the gist of the present invention is the following general formula (I):

[0006]

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Wherein R ¹ is a C ₁ -C ₄ alkyl group;
Haloalkyl group C ₁ -C _4, a phenyl group or a benzyl group, R ² represents a hydrogen atom, an alkyl group of C ₁ -C _4, a cycloalkyl group or a phenyl group of C ₃ -C _6, X is hydrogen atom, a halogen atom, an alkyl group of C ₁ -C _4, nitro group or cyano group, Y represents a chlorine atom or a bromine atom. ) Represented by the following general formula (II):

[0008]

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(Wherein, R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, a C ₁ -C ₄ alkyl group or a phenyl group, R ⁶ and R ⁷ each independently represent a hydrogen atom, halogen atom, an alkyl group of C ₁ ~C _8, C ₃ ~C cycloalkyl group _6, an alkoxyalkyl group of C ₂ -C _4,
A C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ haloalkoxy group, a nitro group, a trifluoromethyl group, a phenyl group,
Benzyl group, phenoxy group, C ₁ -C ₄ alkylphenoxy group, benzyloxy group, C ₁ -C ₄ alkylamino group, C ₂ -C ₈ dialkylamino group, cyano group, C
Alkylaminocarbonyl group ₂ -C _6, a dialkylamino group of C ₃ -C _11, piperidinocarbonyl group, morpholinocarbonyl group, trimethylsilyl groups, C
_A C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group, or a C ₁ -C ₄ alkylsulfonyl group. ) With a benzylamine represented by the following general formula (III):

[0010]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , and X are the same as defined in the general formulas (I) and (II)
As defined in. Pyrazole-5-
In producing carboxamides, the benzylamines (II) in an amount greater than equimolar to the sum of the 5-pyrazolecarbonyl halides (I) and the equivalent derivatives thereof in the reaction raw materials is used. A method for producing pyrazole-5-carboxamides, which is characterized in that:

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, specific embodiments of the present invention will be described. The amidation reaction of the present invention is shown in the following scheme (R ¹ in the scheme,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and Y are as described above).

[0013]

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The carbonyl halide of the above general formula (I) to be used as a reaction raw material can be prepared by a known method, for example, by the following general formula (V)
I):

[0015]

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(Wherein R ¹ , R ² and X are as defined above). The carboxylic acid (VI) can be produced by chlorination. As the chlorinating agent, for example, thionyl chloride, phosgene and the like are used. The carbonyl halides can be used after purification such as distillation. However, as described in the examples of JP-A-2-49771, the method of using the crude product after the reaction as it is does not cause purification loss and the process is also simple. It is preferable because it is simple. In this chlorination reaction, the desired carbonyl halides are obtained in high yield, but carboxylic anhydrides (IV) are by-produced as a reaction by-product as shown in the following scheme.

[0017]

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The carboxylic anhydrides (IV), which are by-products of the chlorination reaction, also contribute to the amidation reaction in the next step as shown in the following scheme to produce the desired carboxamides (III). Is slower than the main reaction between carbonyl halides (I) and benzylamines (II).

[0019]

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Therefore, when the equivalent amount of the benzylamines (II) added during the amidation reaction is insufficient, the carboxylic anhydrides (IV) remain in the reaction system, which is composed of an aqueous alkali solution and an aqueous acid solution. It cannot be removed by washing operation alone because it does not dissolve in water. Carboxamides (III)
It becomes impurities in the inside. The carboxylic anhydrides (IV) contained in the product can be removed by repeating purification such as crystallization, but the loss of the target product is large and the yield is reduced.

On the other hand, the equivalent of the benzylamines (II) to be added is determined by the carbonyl halides (I) in the reaction raw materials and the carbonyl halides (I) as in the carboxylic acid anhydrides (IV) shown in the above scheme. ), A derivative of carbonyl halide (I) equivalent to carbonyl halide (I) in the sense that it reacts with benzylamine (II) to form carboxamide (III) (hereinafter referred to as "equivalent derivative"). Is larger than the total equivalent of the above, the carboxylic anhydrides (IV) are consumed in the reaction as in the above scheme.

That is, the number of moles of the benzylamines (II) used is 1 mole of the total number of moles of the carbonyl halides (I) and the equivalent derivatives of the carbonyl halides (I) such as carboxylic anhydrides (IV). More than 1 mol is required, preferably 1.01 to 1.5 mol, and more preferably 1.01 to 1.1 mol in consideration of economy. Since the only equivalent derivative contained as an impurity in the carbonyl halides (I) as a reaction raw material is usually only the carboxylic anhydrides (IV), the above is usually expressed by the following formula (unit is mol). expressed.

[0023]

[Benzylamines (II)]: [carbonyl halides (I) + carboxylic anhydrides (IV)] = 1.0
The 1-1.5: 1 benzylamines (II) may be added or added dropwise in excess from the beginning of the reaction, but initially, an equivalent amount thereof is added and reacted, and the remaining carbonyl halides (I) and Depending on the carboxylic anhydrides (IV), the remaining excess may be added or added dropwise.

The main by-products of this amidation reaction include:
Carboxylic acids (VI) by-produced by hydrolysis of carbonyl halides (I) and amidation reaction of carboxylic anhydrides (IV), benzylamines (II) in excess, inorganic salts and the like, All of these by-products can be easily removed by a post-treatment washing operation. Specifically, the carboxylic acids (VI) can be dissolved and removed as an alkali salt in the alkaline aqueous layer in the reaction system, and the benzylamines (II) are washed with an aqueous acidic solution and, if necessary, water in the post-treatment. This can be removed as a hydrochloride. Therefore, a high-quality product carboxamides (III) can be easily obtained by concentrating the organic layer after the washing operation and distilling off the solvent. Further, the loss of the target product in the washing operation is very small, and the carboxamides (III) can be obtained in high yield.

The organic solvent used in carrying out the process of the present invention is not particularly limited as long as it is an inert solvent for the carbonyl halides (I) as the raw materials. Among them, toluene, xylene, chlorobenzene And the like are preferred. The amount of the organic solvent used is required to dissolve the raw material benzylamines (II) and the target carboxamides (III) so as to facilitate the separation operation after the reaction. However, use of more than the required amount is not preferable in terms of pot efficiency and cost. It may be a useful method to carry out a liquid separation operation under heating to reduce the amount of solvent used.

Examples of the aqueous alkaline solution include inorganic bases such as hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate. And sodium hydroxide and sodium carbonate are preferred from the viewpoint of cost. The amount of these bases used is such that an equimolar amount of acid is by-produced with respect to the starting carbonyl halides (I) during the reaction.
Usually, about 1.0 to 2.0 equivalents are preferable, but it is particularly important that the aqueous layer after the reaction shows alkalinity. That is, the alkaline aqueous layer after the reaction has a role of removing acidic impurities such as carboxylic acids (VI) as hydrochlorides to the aqueous layer side.

In the method of the present invention, the reaction temperature is usually 0 to
It is in the range of 100C, preferably 10-60C. Since the carbonyl halide (I), which is a raw material of this reaction, has a high reactivity and this reaction is an exothermic reaction, the reaction temperature is usually controlled while the carbonyl halide (I) is added dropwise under cooling. The time for dropping the carbonyl halide (I) is not particularly limited as long as the exothermic reaction can be controlled, but is usually about 2 to 10 hours including the reaction time after dropping.

[0028]

EXAMPLES Hereinafter, specific embodiments of the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist thereof. Example 1 90 g of water was placed in a 300 ml separable flask equipped with a condenser, a tube pump line, a thermometer, and a stirring blade.
20 g of 25% aqueous sodium hydroxide solution (NaOH: 1
25 mmol), toluene 125 ml, 4- (p-tolyloxy) benzylamine 25.5 g (purity 98.6)
%, 118 mmol) was added. The mixture is stirred at 30 to 35 ° C. until the raw materials are sufficiently dissolved, and 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride 25 is stirred.
g (acid chloride (88.6%), acid anhydride (7%); acid chloride (107 mmol), acid anhydride (5 mmol)
1)) was added dropwise over about 30 minutes while controlling the reaction temperature to be 35 to 40 ° C. [Benzylamines:
Carbonyl halides = 1.05: 1 (molar ratio)] After the dropwise addition, the mixture was stirred at 40 ° C. for 2 hours to complete the reaction. After the reaction, the organic layer was analyzed by liquid chromatography, and it was confirmed that the benzylamine remained.
After the reaction, the stirring was stopped, the liquid was separated, the lower alkaline aqueous layer was extracted, and the organic layer was washed with 100 g of water. Thereafter, the organic layer was washed with 100 g of a 3% hydrochloric acid aqueous solution, and further washed with 100 g of water.
g was washed three times. The obtained organic layer was concentrated under reduced pressure, and toluene as a solvent was distilled off to obtain a target product in a molten state. The melt was taken out and cooled, and 43.0 g of 4-chloro-3-ethyl-1-methyl-N- [4- (p-tolyloxy) benzyl] pyrazole-5-carboxamide as a pale yellow solid (mp. 88 ° C.). (112mmo
1) was obtained. When the purity of the obtained product was analyzed by liquid chromatography, it was of high quality of 99.8%.

Example 2 Using the same apparatus as in Example 1, 90 g of water and 20 g of a 25% aqueous sodium hydroxide solution (NaOH: 125 mmol)
1), 125 ml of toluene and 19.3 g of 4-t-butylbenzylamine (purity 99.8%, 118 mmol) were added. Then, as in Example 1, 4-chloro-3-
Ethyl-1-methyl-5-pyrazolecarboxylic acid chloride 25 g (acid chloride (88.6%), acid anhydride (7
%); Acid chloride (107 mmol), acid anhydride (5 m
mol)) was added dropwise. [Benzylamines: carbonyl halides = 1.05: 1 (molar ratio)] The reaction and post-treatment were carried out in the same manner as in Example 1 to obtain 37.0.
g of N- (4-t-butylbenzyl) -4-chloro-3
-Ethyl-1-methylpyrazole-5-carboxamide (light yellow solid, mp. 62 ° C) was obtained. When the purity of the obtained material was analyzed by liquid chromatography,
The quality was as high as 99.5%.

Comparative Example 1 A reaction was carried out using the same apparatus and the same quality raw materials as in Example 1. As described in Example 1, 90 g water, 25%
-20 g of aqueous sodium hydroxide solution, 125 ml of toluene
After addition of 4- (p-tolyloxy) benzylamine 2
3.0 g (106 mmol) were added. Then, as in Example 1, 4-chloro-3-ethyl-1-methyl-5
-Pyrazolecarboxylic acid chloride 25 g (acid chloride (88.6%), acid anhydride (7%); acid chloride (10
7 mmol) and acid anhydride (5 mmol)) were added dropwise.
[Benzylamines: carbonyl halides = 0.9
5: 1 (molar ratio)] The reaction and post-treatment were the same as those in Example 1,
g of solid were obtained. When the purity of the obtained product was analyzed by liquid chromatography, the purity of the target product was 96.
At 6%, acid anhydride was detected as the main impurity.

Example 3 In the same manner as in Comparative Example 1, 4- (p-tolyloxy)
For 23.0 g (106 mmol) of benzylamine,
25 g of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride (acid chloride (88.6)
%), Acid anhydride (7%); acid chloride (107 mmol)
l), acid anhydride (5 mmol)) was added dropwise,
The reaction was carried out with stirring at ℃. [Benzylamines: carbonyl halides = 0.95: 1 (molar ratio)] After the reaction, the organic layer was analyzed by liquid chromatography. As a result, the above benzylamines were not detected. Things were confirmed.

Thereafter, 2.6 g (12 mmol) of 4- (p-tolyloxy) benzylamine was added, and the reaction was further performed for 2 hours. [Benzylamines (total use amount): carbonyl halides = 1.05: 1 (molar ratio)] After the reaction, the organic layer was analyzed by liquid chromatography, and it was confirmed that the benzylamines remained.

The post-treatment was performed in the same manner as in Comparative Example 1,
0.0 g of a solid was obtained (92.5% yield). When the purity of the obtained product was analyzed by liquid chromatography, it was of high quality of 99.8%. Comparative Example 2 A reaction was carried out using the same apparatus and the same quality raw materials as in Example 2. As described in Example 2, 90 g of water, 25%-
After adding 20 g of an aqueous sodium hydroxide solution and 125 ml of toluene, 17.3 g of 4-t-butylbenzylamine (1
06 mmol) was added. Then, similarly to Example 2, 25 g of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride (acid chloride (88.6)
%), Acid anhydride (7%); acid chloride (107 mmol)
l), acid anhydride (5 mmol)) was added dropwise. [Benzylamines: carbonyl halides = 0.95: 1 (molar ratio)] The reaction and post-treatment were carried out in the same manner as in Example 1 and were 37.0.
g of solid were obtained. When the purity of the obtained product was analyzed by liquid chromatography, the purity of the target product was 95.
At 0%, acid anhydride was detected as the main impurity.

[0034]

Industrial Applicability According to the present invention, pyrazole-5-carboxamides, which are compounds useful as active ingredients such as pharmaceuticals and agricultural chemicals, particularly insecticides and acaricides, can be produced in high yield and high quality.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Shigenori Kawamura 1-1 Kurosaki Castle Stone, Yawatanishi-ku, Kitakyushu-shi, Fukuoka F-term in Mitsubishi Chemical Co., Ltd. Kurosaki Plant (Reference) 4H039 CA71 CE90

Claims (5)

[Claims] 1. The following general formula (I): (Wherein, R ¹ represents a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a phenyl group or a benzyl group,
R ² is a hydrogen atom, a C ₁ -C ₄ alkyl group, C ₃ -C ₆
Of a cycloalkyl group or a phenyl group, X represents a hydrogen atom, a halogen atom, an alkyl group of C ₁ -C _4, nitro group or cyano group, Y represents a chlorine atom or a bromine atom. 5-pyrazolecarbonyl halides represented by the following general formula (II): (Wherein, R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, a C ₁ -C ₄ alkyl group or a phenyl group,
R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₈ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkoxyalkyl group, a C ₁ -C 4
₄ alkoxy groups, C ₁ -C ₄ haloalkoxy groups, nitro groups, trifluoromethyl groups, phenyl groups, benzyl groups, phenoxy groups, C ₁ -C ₄ alkylphenoxy groups,
Benzyloxy group, C ₁ -C ₄ alkylamino group, C
Dialkylamino group ₂ -C _8, cyano group, C ₂ -C ₆
Alkylaminocarbonyl group, a dialkylamino group of C ₃ -C _11, piperidinocarbonyl group, morpholinocarbonyl group, trimethylsilyl group, C ₁ -C ₄
Shows an alkylthio group, an alkylsulfinyl group having C ₁ -C ₄ or an alkylsulfonyl group having C ₁ -C _4,. ) With a benzylamine represented by the following general formula (II):
I): (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
And X are as defined in the above general formulas (I) and (II). In producing the pyrazole-5-carboxamides represented by the formula), the benzyl is used in an amount greater than the equimolar amount based on the total amount of the 5-pyrazolecarbonyl halides (I) and the equivalent derivatives thereof in the reaction raw materials. Pyrazole-5 characterized by using amines (II)
A method for producing carboxamides. 2. The following general formula (IV) wherein the 5-pyrazolecarbonyl halide (I) as a reaction raw material is an equivalent derivative thereof as an impurity: (Wherein R ¹ , R ² and X are as defined in the above general formula (I)), which contains a 5-pyrazolecarboxylic anhydride represented by the formula (1).
A method for producing 5-carboxamides. 3. The method according to claim 1, wherein the reaction solution after the reaction is separated into an organic solvent layer and an aqueous solution layer, and the obtained organic solvent layer is washed with an acidic aqueous solution.
A method for producing 5-carboxamides. 4. A post-treatment step after the reaction, wherein a purification operation other than an acid washing operation and a water washing operation is not performed.
3. The method for producing a pyrazole-5-carboxamide according to any one of the above items 3. 5. The above-mentioned pyrazole-5-carboxamides (III) are represented by the following general formula (V): (Wherein R ⁸ represents a t-butyl group or a p-tolyloxy group.) The pyrazole- according to any one of claims 1 to 4, which is a pyrazole-5-carboxamide.
A method for producing 5-carboxamides.