JPH09323973A - Production of amide-based compound or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply produce an amide-based compound useful as an active component of a harmful animal-controlling agent in a high yield by using a haloalkylpyridine-carboxylic acid halide and methyleneaminoacetonitrile as raw materials. SOLUTION: (A) A compound of formula I (Y is a haloalkyl; Hal is a halogen) is reacted with (B) a compound of formula II to obtain (C) an N(cyanomethyl)-N-(halomethyl)-4-haloalkylpyridine-3-calboxylic acid amide. Then, the component C is hydrolyzed to obtain the objective amide-based compound of formula III or its salt after passing through (D) an N-(cyanomethyl)- N-(hydroxymethyl)-4haloalkylpyridine-3-carboxylic acid amide. By the process, the objective compound can readily and inexpensively be produced in a high yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention uses 4-haloalkylpyridine-3-carboxylic acid halide and methyleneaminoacetonitrile as raw materials to produce an amide compound or a salt thereof useful as an active ingredient of a pest control agent. Regarding the method.

[0002]

2. Description of the Related Art The above-mentioned amide compounds or salts thereof, 4
The production method using -haloalkylpyridine-3-carboxylic acid halide and specific amines as starting materials is described in JP-A-6-3.
21903. However, the amines that are the raw materials for this method are often unstable,
Since it is necessary to take measures such as producing the amines in the reaction step and using the amines in excess, the cost becomes high. Further, JP-A-59-7197 describes a method for producing N-phosphonomethylglycine useful as an active ingredient of a herbicide, using a specific acyl halide and methyleneaminoacetonitrile as raw materials.
A method for producing the amide compound of the present invention or a salt thereof is not described.

[0003]

The problem to be solved by the present invention is to produce a target compound in a high yield by a simple reaction process using a stable raw material at a low cost.

[0004]

The present invention has the general formula (V);

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A process for producing an amide compound represented by the formula (wherein Y is a haloalkyl group) or a salt thereof, wherein (i) the general formula (I);

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A compound represented by the formula (wherein Y is a haloalkyl group and Hal is a halogen atom);

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The compound represented by the general formula
(III) ；

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(In the formula, Y is a haloalkyl group, and Ha is
1 is a halogen atom), the first step for producing N- (cyanomethyl) -N- (halomethyl) -4-haloalkylpyridine-3-carboxylic acid amide, (ii) compound of general formula (III) Is hydrolyzed to give a compound of general formula (IV);

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Via the N- (cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide represented by the formula (Y is a haloalkyl group), the general formula (V ) The method for producing the amide compound or a salt thereof, which comprises the second step of producing the compound).

General formulas (I), (III), (IV) and (V)
Examples of the haloalkyl group represented by Y include CF ₃ , C
HF ₂ , CF ₂ Cl, CFCl ₂ , CCl ₃ , CH ₂ C
_{F 3, CF 2 CF 3,} CHBr 2, CH 2 Br C 1-2, such as a haloalkyl group of halogen atom 1-5 is desirable, a trifluoromethyl group is particularly desirable.
The halogen atom represented by Hal in the general formulas (I) and (III) is preferably fluorine, chlorine or bromine, but chlorine is particularly preferable. Further, the compound of the formula (II) is a trimer, and is actually a compound which should be named 1,3,5-tricyanomethylhexahydro-1,3,5-triazine, Is called by the name of methyleneaminoacetonitrile which is a monomer.

The method for producing the amide compound or its salt according to the present invention will be described in detail below.

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The amount of the compound of the general formula (I) and the compound of the formula (II) used in the reaction of the first step depends on the presence or absence of the compound of the general formula (I), the presence or absence of a solvent, the type thereof, the reaction conditions and the like. Differently, it cannot be specified unconditionally, but is usually 0.3 to 0.5 mol (0.9 to 1.5 equivalent), preferably 0.33 to 0.4, relative to 1 mol of the compound of the general formula (I).
The compound of formula (II) is used in a molar ratio (1.0 to 1.2 equivalents).

It is desirable to use a solvent in the first stage reaction. Specifically, an aprotic solvent can be used, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; ethylene dichloride, propylene dichloride, methylene chloride and chloroform. Halogenated hydrocarbons such as; ethers such as diethyl ether, dibutyl ether, tetrahydrofuran; esters such as ethyl acetate, methyl acetate;
Ketones such as acetone and methyl ethyl ketone; N, N
-Aprotic polar solvents such as dimethylformamide, acetonitrile and dioxane can be used. These solvents can be used alone or in combination. The amount of the solvent used in the reaction of the first step cannot be specified unconditionally because it depends on other reaction conditions, but it is usually 1 to 20 ml, preferably 2 to 5 ml of the solvent per 1 g of the compound of the general formula (I). Is used.

The reaction temperature and reaction time of the first step reaction cannot be unconditionally defined because they are determined by other reaction conditions, but the reaction temperature is usually 0 to + 150 ° C., preferably 40.
The reaction time is usually 0.1 to 24 hours, preferably 0.5 to 3 hours.

In the present invention, the reaction solution containing the compound of the general formula (III) after the completion of the reaction of the first step can be continuously used as it is for the reaction of the second step and thereafter, and the reaction solution is usually used. After the solvent is distilled off, washing and drying are carried out, the compound of the general formula (III) can be isolated and used for the reaction in the second step and thereafter. In addition, N- (cyanomethyl) -N- (halomethyl) which is a compound of general formula (III)
-4-Haloalkylpyridine-3-carboxylic acid amide is one of the amide compounds described in JP-A-6-321903.

Incidentally, in setting various conditions in the reaction of the first step, that is, the amounts of the compounds of the general formulas (I) and (II), the types and amounts of the solvents, the reaction temperature and the reaction time, respectively, The values can be appropriately selected and combined from the values in the normal range and the values in the desired range shown for each condition.

The second stage reaction is a reaction in which the compound of the general formula (III) is hydrolyzed to produce the final compound of the general formula (V) via the compound of the general formula (IV). is there.
The reaction temperature and reaction time of the second step reaction cannot be unconditionally defined because they are determined by other reaction conditions, but the reaction temperature is usually 0 to + 110 ° C., and the reaction time is usually 10 minutes to 24 minutes.
Time. As the method for carrying out the reaction in the second step, the compound of the general formula (IV) and / or the general formula (V) is obtained by hydrolyzing the compound of the general formula (III) under acidic conditions.
The compound of the general formula (III) is hydrolyzed under acidic conditions to once produce the compound of the general formula (IV), and the compound of the general formula (V) is neutralized with a base. And a method of producing the compound of general formula (V) by hydrolyzing the compound of general formula (III) in the presence of a base. The details of the reaction vary depending on each method, and are described below.

As a method for producing the compound of the general formula (IV) and / or the compound of the general formula (V) by hydrolyzing the compound of the general formula (III) under acidic conditions, There is a method in which only the water is added to the compound of 1) to perform the hydrolysis, and a method in which water and an acid are added to the compound of the general formula (III) to perform the hydrolysis. In the former case, the compound of general formula (III) reacts with water, and hydrochloric acid is gradually liberated.
The reaction solution gradually becomes acidic. Therefore, the hydrolysis can be carried out under acidic conditions. On the other hand, in the latter case, since the reaction liquid is acidic from the initial stage of the reaction, hydrolysis can be carried out under acidic conditions. Examples of the acid that can be used in the latter method include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid; organic strong acids such as methanesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid; stearic acid, palmitic acid, acetic acid. Organic weak acids such as can be used,
It is desirable to use mineral acids or strong organic acids. Further, these acids can be used alone or in combination.

When the compound of general formula (III) is hydrolyzed under acidic conditions, the compound of general formula (IV) is usually produced.
However, depending on the reaction conditions, the reaction of forming the compound of general formula (IV) and the reaction of removing formaldehyde from the formed compound of general formula (IV) proceed at the same time. A mixture with a compound of general formula (V) or a compound of general formula (V) is formed. The compound of general formula (V) or the mixture of the compound of general formula (IV) and the compound of general formula (V) thus formed can be further hydrolyzed to produce the compound of general formula (V). The reaction conditions for hydrolysis of the compound of general formula (III) under acidic conditions can be set within the ranges of the above-mentioned usual reaction temperature and reaction time.

When the compound of the general formula (III) is hydrolyzed under acidic conditions to produce the compound of the general formula (IV), the solvent containing the compound of the general formula (IV) is usually distilled off. After being subjected to operations such as washing, drying, etc., the compound of general formula (IV) can be isolated. N- which is a compound of general formula (IV)
(Cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide is one of the amide compounds described in JP-A-6-321903.

As in the above method, the compound of the general formula (III) is hydrolyzed under acidic conditions, or the compound of the general formula (IV) or the compound of the general formula (IV) and the general formula (V). After producing a reaction solution containing a mixture with, the reaction mixture is neutralized with a base, and a reaction for eliminating formaldehyde while maintaining a weakly acidic to weakly basic pH of about 6 to 9 is also carried out. Compounds of formula (V) or salts thereof can be prepared. Bases that can be used in this way include:
Examples thereof include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate and ammonia. The reaction conditions for the reaction for eliminating formaldehyde in the latter half of this method cannot be clearly defined because they depend on the reaction conditions for hydrolysis of the compound of general formula (III) under acidic conditions. However, the reaction conditions throughout this process can be set within the usual reaction temperature and reaction time ranges described above. Further, a weakly acidic to weakly basic reaction liquid obtained by adding water (and a base) to the compound of the general formula (IV) once isolated may similarly be used to proceed the reaction for elimination of formaldehyde. .

The compound of the general formula (V) or a salt thereof can also be produced by the method of hydrolyzing the compound of the general formula (III) in the presence of a base as in the above-mentioned method. That is, when water and a base are added to a compound of the general formula (III) to carry out hydrolysis, the compound of the general formula (III) reacts with water, and hydrochloric acid is gradually liberated, while the base is gradually released. Since this is neutralized, the reaction can be carried out while maintaining the pH in the reaction solution at a weak acidity of about 6 to 9 to a weak basicity. Examples of the base that can be used in this method include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, ammonia and the like.
The compound of the general formula (V) is considered to be produced via the compound of the general formula (IV).
The reaction in which formaldehyde is eliminated from the compound of general formula (IV) has a higher reaction rate than the reaction in which the compound of general formula (IV) is produced, so that it appears that only the compound of general formula (V) is produced. . Further, depending on the reaction conditions, a decomposition product of the compound of general formula (V) is also produced.

In the reaction of the second step, the aprotic solvent usable in the reaction of the first step is usually 0.1 to 100 ml per 1 g of the compound of the general formula (III) or the general formula (IV).
Even if hydrolysis is carried out in combination at a ratio of 1, the yield of the compound of the general formula (IV) and / or the compound of the general formula (V) is not adversely affected. Therefore, a predetermined amount of the solvent may be already used in the reaction of the first step, and the reaction solution containing the solvent after the completion of the reaction of the first step may be directly subjected to the reaction of the second step for hydrolysis.

In the second stage hydrolysis reaction,
Various conditions, i.e. the amount of compound of general formula (III) used,
When setting the presence or absence of acid, base or solvent and their amounts, reaction temperature and reaction time,
It is possible to appropriately select and combine the values in the normal range and the values in the desired range shown for each condition.

After completion of the hydrolysis reaction, the desired compound of the general formula (V) or a salt thereof is subjected to post-treatment such as usual solid-liquid separation, solvent removal, washing, and drying, for the reaction product. can get.

Next, some of the embodiments of the present invention will be exemplified.

(1) The compound of the general formula (I) is reacted with the compound of the formula (II) to prepare the compound of the general formula (III), the compound of the general formula (III) is hydrolyzed. A method for producing an amide compound or a salt thereof, which comprises the second step of producing a compound of the general formula (V) through decomposition and production of the compound of the general formula (IV). (2) The compound of the general formula (IV) is obtained by hydrolyzing the compound of the general formula (III).
A method for producing an amide compound or a salt thereof, which comprises producing a compound of the general formula (V) via the compound of (3) A method for producing an amide compound or a salt thereof, which comprises removing formaldehyde from a compound of the general formula (IV) to produce a compound of the general formula (V). (4) The compound of general formula (IV) is obtained by hydrolyzing the compound of general formula (III).
A method for producing N- (cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide for producing the compound of 1.

(5) Method for producing N- (cyanomethyl) -N- (halomethyl) -4-haloalkylpyridine-3-carboxylic acid amide by reacting the compound of general formula (I) with the compound of formula (II) . (6) The method of (1), wherein the reaction of the first step is carried out in the presence of a solvent. (7) The method of (5), wherein the reaction is carried out in the presence of a solvent.

(8) A compound of the general formula (IV) and / or a compound of the general formula (V) is produced by hydrolyzing the compound of the general formula (III) under acidic conditions (1),
The method of (2) or (4). (9) A compound of general formula (V) is produced by hydrolyzing a compound of general formula (III) under acidic conditions to once produce a compound of general formula (IV), and neutralizing this with a base. The method of (1) or (2). (10) The method of (1) or (2) for producing a compound of general formula (V) by hydrolyzing a compound of general formula (III) in the presence of a base.

As an embodiment of the present invention, the reaction conditions described above, that is, the solvent and the amount thereof used in the first step reaction, the acid and / or base and the amount thereof used in the second step reaction, and the general formula ( I) and the amount of the compound of formula (II) used, the reaction temperature in the first step, the reaction temperature in the second step, the general formula (I
II) and / or the presence or absence of the compound of the general formula (IV) can be appropriately combined.

[0031]

The present invention will be described in more detail with reference to the following Examples, which do not limit the present invention.

Example 1 (1) N- (chloromethyl) -N- (cyanomethyl)-
4-Trifluoromethylpyridine-3-carboxylic acid ami
Synthesis of 4-defluoromethylpyridine-3-carboxylic acid chloride 209.5 g, methyleneaminoacetonitrile 7
1.4 g was added to 1048 ml of toluene and heated under reflux for 3 hours. After completion of the reaction, toluene was distilled off under reduced pressure to obtain crude N
-(Chloromethyl) -N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide 27
0.2 g was obtained. The melting point of this product is 104 to 120.5.
C., and the structure is confirmed by NMR and mass spectrum.

(2) N- (cyanomethyl) -N- (hydr
Roxymethyl) -4-trifluoromethylpyridine-3
- synthetic crude N- (chloromethyl) carboxylic acid amide -N- (cyanomethyl) -4-
Trifluoromethylpyridine-3-carboxylic acid amide 1
0 g was added to 50 ml of water, and 14 ml of concentrated hydrochloric acid was further added. After stirring overnight at room temperature, the reaction solution was extracted with ethyl acetate, the solvent was evaporated, and N- (cyanomethyl) -N- (hydroxymethyl) -4-trifluoromethylpyridine-3 was extracted.
-7.17 g of carboxylic acid amide was obtained. The melting point of this product was 125.4 to 126.4 ° C.

(3) N- (Cyanomethyl) -4-trif
Synthesis of luoromethylpyridine -3-carboxylic acid amide N- (cyanomethyl) -N- (hydroxymethyl) -4
2.6 g of trifluoromethylpyridine-3-carboxylic acid amide was added to 13 ml of water, and after cooling with ice, 1.2 g of a 5% sodium carbonate aqueous solution was added. After stirring at room temperature for 1 hour, the crystals were collected by filtration to obtain 1.9 g of N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide.

Example 2 N- (cyanomethyl) -4-trifluoromethylpyridi
Synthesis of N-3-carboxylic acid amide Crude N- (chloromethyl) -N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide obtained in the same manner as in Example 1 (1) 2. 8g of water 14m
In addition to 1., 1.26 g of concentrated hydrochloric acid was further added. 3 at room temperature
After reacting for 0 minutes, a 10% sodium carbonate aqueous solution was added to neutralize, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, the solvent was distilled off, and N- (cyanomethyl)-
2.10 g of 4-trifluoromethylpyridine-3-carboxylic acid amide was obtained.

Example 3 N- (Cyanomethyl) -4-trifluoromethylpyridi
Synthesis of benzene -3-carboxylic acid amide 7.1 g (0.105 equivalent) of methyleneaminoacetonitrile was added to 90 ml of toluene, and 21 g of 4-trifluoromethylpyridine-3-carboxylic acid chloride (0.
A solution of 1 mol) in 15 ml of toluene was added dropwise, and the mixture was reacted at 90 ° C. for 3 hours. Further, 0.7 g (0.01 equivalent) of methyleneaminoacetonitrile was added, and the mixture was heated under reflux for 2 hours. After allowing to cool, 42 ml of water was added, and the mixture was reacted at 50 to 53 ° C for 1 hour. After completion of hydrolysis, 10% -sodium hydroxide aqueous solution was added for neutralization, and the mixture was further stirred at room temperature for 1 hour.
The obtained crystals were collected by filtration and N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide 2
0.2 g was obtained. Then, the filtrate was extracted with ethyl acetate and the solvent was removed to obtain 2.8 g of N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide.

Example 4 N- (Cyanomethyl) -4-trifluoromethylpyridi
Synthesis of N-3-carboxylic acid amide Crude N- (chloromethyl) -N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide obtained in the same manner as in Example 1 (1) 8. 6 g of water 43 m
1 and reacted at room temperature overnight. The reaction solution was heated to 50 ° C. and reacted for 3.5 hours, then heated to 95 ° C. and further reacted for 2 hours. After the completion of hydrolysis, the mixture was cooled with ice, and the obtained crystals were collected by filtration to obtain N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide (3.93 g). Then, the filtrate was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, the solvent was removed, and N- (cyanomethyl) was added.
1.59 g of -4-trifluoromethylpyridine-3-carboxylic acid amide was obtained.

Example 5 N- (Cyanomethyl) -4-trifluoromethylpyridi
Synthesis of N-3-carboxylic acid amide Crude N- (chloromethyl) -N- (cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide obtained in the same manner as in Example 1 (1) 2. 8g of water 14m
The resulting mixture was added to 1 of the above and reacted at 55 ° C. for 30 minutes, 10% -sodium carbonate aqueous solution was added for neutralization, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, the solvent was distilled off, and N
2.24 g of-(cyanomethyl) -4-trifluoromethylpyridine-3-carboxylic acid amide was obtained.

[0039]

According to the method of the present invention, the compound of the general formula (II) is reacted with the compound of the general formula (II).
It comprises a first step for producing a compound of I), a second step for producing a compound of general formula (V) via hydrolysis of a compound of general formula (III) and a compound of general formula (IV) By the reaction, the desired amide compound can be easily produced. In this method, the target compound can be produced in a high yield by using a raw material which is lower in cost than conventional ones and by a simple reaction step.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Fumihiro Fukui 2-3-1, Nishi-Shibukawa, Kusatsu City, Shiga Ishihara Sangyo Co., Ltd.

Claims (4)

[Claims] 1. A compound represented by the general formula (V): A method for producing an amide compound represented by the formula (wherein Y is a haloalkyl group) or a salt thereof, comprising: (i) the general formula (I); (In the formula, Y is a haloalkyl group and Hal is a halogen atom), and a compound represented by the formula (II); A compound represented by the general formula (III): (In the formula, Y is a haloalkyl group and Hal is a halogen atom). N- (cyanomethyl) -N-
The first step for preparing (halomethyl) -4-haloalkylpyridine-3-carboxylic acid amide, (ii) hydrolyzing the compound of general formula (III) to give general formula (IV); (In the formula, Y is a haloalkyl group) N-
Of the amide-based compound or a salt thereof, which comprises the second step for producing the compound of general formula (V) via (cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide; Production method. 2. A compound represented by the general formula (V): A method for producing an amide compound represented by the formula (wherein Y is a haloalkyl group) or a salt thereof, wherein
I); (In the formula, Y is a haloalkyl group and Hal is a halogen atom). N- (cyanomethyl) -N-
(Halomethyl) -4-haloalkylpyridine-3-carboxylic acid amide is hydrolyzed to give a compound of general formula (IV); (In the formula, Y is a haloalkyl group) N-
(Cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide is used to produce a compound of the general formula (V), wherein the amide compound or a salt thereof is produced. Method. 3. A compound represented by the general formula (V): A method for producing an amide compound represented by the formula (wherein Y is a haloalkyl group) or a salt thereof, wherein
V); (In the formula, Y is a haloalkyl group) N-
A method for producing the amide compound or a salt thereof, comprising removing formaldehyde from (cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide. 4. A compound represented by the general formula (IV): (In the formula, Y is a haloalkyl group) N-
A method for producing (cyanomethyl) -N- (hydroxymethyl) -4-haloalkylpyridine-3-carboxylic acid amide, which comprises a compound represented by the general formula (III): (In the formula, Y is a haloalkyl group and Hal is a halogen atom). N- (cyanomethyl) -N-
(Halomethyl) -4-haloalkylpyridine-3-carboxylic acid amide is hydrolyzed, wherein the N-
(Cyanomethyl) -N- (hydroxymethyl) -4-
A method for producing a haloalkylpyridine-3-carboxylic acid amide.