JPH0676389B2 - Process for producing imidazole derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to an improved process for producing an imidazole derivative represented by the following formula (IV), which is useful as an agricultural / horticultural fungicide or nematicide.

(Prior Art) The following method is known as a method for producing the imidazole derivative (IV).

(1) N-substituted amino acid ester (I) is reacted with phosgene or trichloromethyl chloroformate in the presence of an organic base in an aprotic solvent to give compound (II), which is then converted into an organic base or an inorganic base. Method of reacting with imidazole (III) in the presence of aprotic solvent (JP-A-59-134791, JP-A-59-141562, JP-A-60-26)
0572, JP-A-60-260561, JP-A-60-109568) (2) Reaction of imidazole (III) with phosgene or trichloromethylchloroformate in the presence of an organic base in an aprotic solvent. Let the formula (In the formula, R ³ represents the same meaning as described above) and carbonylbisimidazole, and then
A method of reacting this with N-substituted amino acid ester (I) (JP-A-58-150590, JP-A-59-134791, JP-A-SHO).
59-141562) The yield of the imidazole derivative (IV) according to the first and second methods is as low as 30 to 70% based on the N-substituted amino acid ester (I).

Further, in the first method, a stoichiometric amount or a 3-fold molar amount of a tertiary amine is required in the first step, and then a stoichiometric amount or a 4-fold molar amount of a tertiary amine is required in the second step, and When imidazole itself is used as a dehydrochlorination agent, 3
~ 6 times the molar amount is used. Alternatively, an example of using an inorganic base as a dehydrochlorination agent in the second step is also known,
In an aprotic solvent, since the solubility of the inorganic base is small, it does not work effectively and requires an excessive amount of imidazole. Thus, it is necessary to excessively use such expensive tertiary amine or imidazole. Not industrially preferable.

Since the second method is a reaction using carbonylbisimidazole, imidazole requires 2 times or more moles of the N-substituted amino acid ester in terms of reaction mechanism, and is different from the first method in terms of recovery of imidazole. Similarly, it has an unfavorable industrial problem. In both the first and second methods, hydrogen chloride generated during the reaction becomes 2 equivalents with respect to the N-substituted amino acid ester (I), and these are treated with an organic base or excess imidazole in an aprotic solubilization. There was a problem with these processes in order to capture. Further, the reaction system became a thick slurry, and there were problems in the progress of the reaction and the acquisition of products.

(Problems to be Solved by the Invention) The present inventors have found the problems of the above-mentioned conventional methods, namely, low yield,
As a result of intensive studies to solve the problems such as the use of a large amount of organic base and imidazole and the complexity of operation, an industrially advantageous production method is provided here.

(Means for Solving the Problems) (In the formula, Y may be substituted with a lower alkyl group 2-
A furyl group, a 2-tetrahydrofuryl group, a 2-thienyl group, a halogen atom, a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, R ¹ represents a hydrogen atom or a lower alkyl group, R ² Represents a lower alkyl group, an alkenyl group, a cycloalkyl group or an alkoxyalkyl group, and n represents 0 or 1), and an N-substituted amino acid ester represented by
The reaction is carried out in the presence of an inorganic base in a two-layer system solvent consisting of water and a poorly water-soluble aprotic solvent, (Wherein Y, R ¹ , R ² and n have the same meanings as described above) are obtained in a solvent layer, and the compound (II) is then dissolved in a poorly water-soluble aprotic solvent. , In the presence of an organic base, the formula (Wherein R ³ represents a hydrogen atom or a methyl group), and the compound represented by the formula: (In the formula, Y, R ¹ , R ² , R ³ and n have the same meanings as described above).

The feature of the method of the present invention is that an inorganic base is used as a deoxidizing agent in the first step, and it is composed of water and an aprotic solvent hardly soluble in water.
The reaction is performed in a layered solvent, and after the reaction is completed, the aqueous layer is separated,
The purpose is to remove the formed inorganic salt and the remaining inorganic base dissolved in the aqueous layer out of the system, thereby avoiding the excessive addition of the organic amine and imidazole in the second step.

Y of the N-substituted amino acid ester (I) which is a raw material of the present invention includes 2-furyl, 5-methyl-2-furyl, and 2
-Tetrahydrofuryl, 2-thienyl, 3- or 5
-Methyl-2-thienyl, phenyl, phenyl substituted with chloro-, bromo-, fluoro-, methoxy- or methyl at the o-, m- or p-position and the like, and 2-furyl is particularly preferable. Examples of R ¹ include a hydrogen atom, methyl, ethyl, propyl and the like, with ethyl being particularly preferred. R ² is methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl, s
a linear or branched C _1-6 lower alkyl group such as ec-pentyl, hexyl, isohexyl; allyl, 2-butenyl, 3-butenyl, methallyl, 2-pentenyl, 3
Such as -pentenyl, 4-pentenyl, 2-hexenyl
A C _3-6 linear or branched lower alkenyl group, a cycloalkyl group such as cyclopentyl or cyclohexyl;
Alternatively, compounds having an alkoxyalkyl group such as ethoxymethyl, methoxyethyl and ethoxyethyl are mentioned, and methyl, isopropyl and 4-pentenyl are particularly preferable.

The first step is performed as follows.

Phosgene is usually used in a proportion of 1.0 to 1.5 mol, preferably 1.0 to 1.3 mol, per 1 mol of N-substituted amino acid ester (I). Phosgene is gaseous, liquid,
Alternatively, it is preferably added in a state of being dissolved in an aprotic solvent which is poorly soluble in water described later.

Examples of the inorganic base used in the reaction include water-soluble inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and the like, and carbonates and hydrogen carbonates are preferable. . These inorganic bases are usually used in an amount of 1 to 2 equivalents, preferably 1.
Use at a ratio of 2 to 1.7 equivalents.

As the poorly soluble aprotic solvent used in the reaction,
Aromatic hydrocarbons such as benzene, toluene, xylene;
Chlorinated hydrocarbons such as chlorobenzene, dichlorobenzene, base methylene, chloroform, carbon tetrachloride and 1,2-dichloroethane; esters such as methyl acetate, ethyl acetate, butyl acetate; diisopropyl ether, dibutyl ether, dimethoxy Examples include ethers such as ethane. The aprotic solvent and water are N-
Usually 0.1 to 1.5 per 1 mol of the substituted amino acid ester,
It is preferably used in an amount of 0.2 to 1. It is possible to use more solvent than this upper limit, but there is no advantage thereby.

The reaction temperature is preferably 0 to 80 ° C., and the reaction time is preferably 0.5 to 5 hours.

The reaction may be carried out in the presence of an inert gas such as nitrogen, argon or helium.

After completion of the reaction in the first step, the compound (II) may or may not be isolated, and can be transferred to the next step as a solution of an aprotic solvent obtained by separating the aqueous layer by a liquid separation operation. Further, if necessary, back extraction with a solvent for the liquid separation layer, washing of the solvent layer with water, dehydration of the solvent layer with a desiccant, and the like may be incorporated.

The second step is carried out as follows.

The imidazole (III) is usually 0.9 to 1.3 mol, preferably 1. mol per mol of the N-substituted amino acid ester (I).
It is used in a proportion of 0 to 1.2 mol. Examples of the organic base used in the reaction include tertiary amines such as triethylamine, tri-n-propylamine, tri-n-butylamine and pyridine. The organic base is usually 1.0 to 1.4 mol, preferably 1.0 to 1.4 mol, based on 1 mol of the N-substituted amino acid ester (I).
Used at a ratio of 1.1 to 1.3 mol.

As a method for carrying out the second step, imidazole (III) which is a reaction raw material and an organic base are added to the aprotic solvent solution of the compound (II) obtained in the first step and reacted, or
Alternatively, the aprotic solvent solution of the compound (II) obtained in the first step may be added to the poorly water-soluble aprotic solvent solution containing imidazole (III) and an organic base for reaction. In the latter case, the amount of solvent used is preferably 0.1 to 0.5 per 1 mol of imidazole (III).

The reaction temperature is advantageously in the range of room temperature to 80 ° C., and the reaction time can be appropriately selected depending on the reaction temperature, but it can be generally selected in the range of 1 to 10 hours.

The reaction may be carried out in the presence of an inert gas such as nitrogen, argon or helium.

The imidazole derivative produced in the present invention can be easily isolated and produced according to known methods, for example, filtration, neutralization, extraction, washing, concentration, recrystallization and the like.

(Example) An example is shown below and the present invention is explained in more detail.

Example 1 In a two-necked four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a gas-blowing tube, 197 g (1 mol) of 2- (N-furfurylamino) butyric acid methyl ester and toluene.
5, 106 g (1 mol) of sodium carbonate and 0.5 of water were added, and the system was cooled with stirring until the temperature in the system reached 5 to 10 ° C. After cooling, 128.7 g (1.3 mol) of phosgene was added to the system at a temperature of 1
It was blown for 1 hour so as not to exceed 5 ° C.
After the completion of blowing, the mixture was further stirred for 1 hour at room temperature, and then the toluene layer was separated and obtained.

Next, the above toluene layer was added to a 2-necked 4-necked flask equipped with a stirrer, a thermometer, and a reflux condenser, and imidazole 68 g (1 mol) and triethylamine 111.3 were added with stirring at room temperature.
After adding g (1.1 mol), it stirred at 40 degreeC for 4 hours.

After completion of stirring, the produced triethylamine hydrochloride was removed by filtration, washed with 0.2 toluene, and the filtrate and washings were combined and chromatographed on the liquid by an internal standard method to obtain 2- [N-furfuryl-N- -(1-Imidazolylcarbonyl) amino] butyric acid methyl ester was quantified. Yield 90.4%.

Example 2 In a 4-necked flask of 2 equipped with a stirrer, a thermometer, a reflux condenser and a gas blowing tube, 251 g (1 mol) of 2- (N-furfurylamino) butyric acid 4-pentenyl ester, 0.5 of toluene and carbonic acid were added. 79.5 g (0.75 mol) of sodium and 0.75 of water were added, and the mixture was stirred at room temperature. Phosgene 118.8g
(1.mol) so that the temperature inside the system does not exceed 35 ° C, 1
It took a while to blow. After the completion of blowing, the mixture was stirred at room temperature for 30 minutes, and then the toluene layer was separated.

Next, in a 4-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 21.4-neck flask was charged with 71.4 g (1.0 g) of imidazole.
5 mol), 111.3 g (1.1 mol) of triethylamine and 0.2 of toluene were added, and the temperature inside the system was kept at 45 to 50 ° C. with stirring. Then, the toluene layer is stirred from the dropping funnel with stirring 45
Add over 3 hours keeping at ~ 50 ° C. After completion of dropping, the mixture was stirred for 1 hour at 45 to 50 ° C.

After the stirring was completed, the produced triethylamine hydrochloride was removed by filtration, washed with 0.2 toluene, and the filtrate and washings were combined and analyzed by liquid chromatography by the internal standard method to obtain 2- [N-furfuryl-N- (1-Imidazolylcarbonyl) amino] butyric acid 4-pentenyl ester was quantified. Yield 93.9%.

Example 3 The procedure of Example 1 was repeated except that methylene chloride was used instead of toluene, and 2- [N-furfuryl-N- (1-imidazolylcarbonyl) amino] butyric acid methyl ester was quantified. . Yield 91.4%.

Example 4 In Example 2, 267 g (1 mol) of 2- (N-furfurylamino) butyric acid n-hexyl ester was used instead of 2- (N-furfurylamino) butyric acid 4-pentenyl ester.
Was carried out in the same manner as in Example 2 except that was used to quantify 2- [N-furfuryl-N- (1-imidazolylcarbonyl) amino] butyric acid n-hexyl ester. Yield 90.2%.

Example 5 In Example 2, 251 g (1 mol) of 2- (N-furfurylamino) valeric acid 2-butenyl ester was used instead of 2- (N-furfurylamino) butyric acid 4-pentenyl ester. Otherwise, the same procedure as in Example 2 is performed and 2- [N-
Furfuryl-N- (1-imidazolylcarbonyl) amino] valeric acid 2-butenyl ester was quantified. Yield 93.0
%.

Example 6 In Example 2, instead of 2- (N-furfurylamino) butyric acid 4-pentenyl ester, 2- [N- (5-
Methylfurfuryl) amino] butyric acid 4-pentenyl ester 265 g (1 mol) was used, and the same procedure as in Example 2 was repeated to give 2- [N- (5-methylfurfuryl) -N- (1-
Imidazolylcarbonyl) amino] butyric acid 4-pentenyl ester was quantified. Yield 91.7%.

Example 7 In Example 1, instead of 2- (N-furfurylamino) butyric acid methyl ester, 255 g of 2- (N-tetrahydrofurfurylamino) butyric acid 4-pentenyl ester was used.
Mol) was used, and the same procedure as in Example 1 was carried out, and 2- [N-
Tetrahydrofurfuryl-N- (1-imidazolylcarbonyl) amino] butyric acid 4-pentenyl ester was quantified. Yield 91.3%.

Example 8 In Example 2, except that 251 g (1 mol) of 3- (N-furfurylamino) butyric acid 4-pentenyl ester was used in place of 2- (N-furfurylamino) butyric acid 4-pentenyl ester. The same procedure as in Example 2 was carried out to quantify 3- [N-furfuryl-N- (1-imidazolylcarbonyl) amino] butyric acid 4-pentenyl ester. Yield 92.5
%.

Example 9 The procedure of Example 2 was repeated except that 86.1 g (1.05 mol) of 2-methylimidazole was used instead of imidazole, and 2- [N-furfuryl-N- (2-methyl-1- Imidazolylcarbonyl) amino] butyric acid 4-pentenyl ester was quantified. Yield 93.5%.

Example 10 In Example 1, 150 g (1.5 mol) of potassium hydrogencarbonate was used instead of sodium carbonate, and 225 g of 2- (N-furfurylamino) butyric acid isopropyl ester was used instead of 2- (N-furfurylamino) butyric acid methyl ester. Example 2 was repeated except that (1 mol) was used, and 2- [N-furfuryl-N- (1-imidazolylcarbonyl) amino] butyric acid isopropyl ester was quantified. Yield 90.2%.

Comparative Example 1 2- (N-furfurylamino) butyric acid methyl ester 197 g (1 mol) and toluene 1 were placed in a 2-necked 4-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a gas blowing tube.
And triethylamine 151.8 g (1.5 mol) were added,
It was cooled with stirring until the temperature in the system reached 5 to 10 ° C.
After cooling, 128.7 g (1.3 mol) of phosgene was blown thereinto over 2 hours while keeping the system temperature below 15 ° C. After the completion of blowing, the mixture was stirred for 1 hour at room temperature.

Next, the gas blowing tube was removed, and imidazole 68 g (1 mol) and triethylamine 111.3 g (1.1
Mol), and the mixture was stirred at 40 ° C. for 4 hours. After completion of stirring, the produced triethylamine hydrochloride was removed by filtration, washed with 0.4 of toluene, and the filtrate and washings were combined and analyzed by liquid chromatography by an internal standard method to obtain 2- [N-furfuryl- N- (1-imidazolylcarbonyl) amino] butyric acid methyl ester was quantified.
Yield 73.6%.

Comparative Example 2 2- (N-furfurylamino) butyric acid 4-pentenyl ester 251 g (1 mol), toluene 0.5, carbonic acid were placed in a 2-necked 4-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a gas blowing tube. 106 g (1 mol) of sodium and water
0.5 was added and the mixture was stirred at room temperature. Phosgene 118.8g (1.2
(Mol) was blown in for 1 hour so that the temperature in the system did not exceed 35 ° C. After the completion of blowing, the mixture was stirred for another 30 minutes at room temperature.

Next, remove the gas blowing tube, and under stirring at room temperature, 168 g (2 mol) of sodium hydrogen carbonate and 74.8 g of imidazole.
After adding (1.1 mol), the mixture was stirred at 40 ° C. for 4 hours. After completion of stirring, the toluene layer was separated, and the aqueous layer was extracted with toluene 0.2. Combine the above toluene layer and extracted toluene layer,
2- [N-furfuryl-N- (1-imidazolylcarbonyl) amino] butyric acid 4-pentenyl ester was quantified. Yield 5.8%.

Front page continuation (72) Inventor Hiroyuki Miyata 5 1978, Kouji, Ube, Yamaguchi Prefecture 5 Ube Kosan Co., Ltd. Ube Laboratory (56) Reference JP-A-60-260572 (JP, A) JP-A-60-260561 (JP, A) JP-A-63-10751 (JP, A)

Claims (1)

[Claims] 1. A formula (In the formula, Y may be substituted with a lower alkyl group 2-
A furyl group, a 2-tetrahydrofuryl group, a 2-thienyl group, a halogen atom, a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, R ¹ represents a hydrogen atom or a lower alkyl group, R ² Represents a lower alkyl group, an alkenyl group, a cycloalkyl group or an alkoxyalkyl group, and n represents 0 or 1), and an N-substituted amino acid ester represented by
The reaction is carried out in the presence of an inorganic base in a two-layer system solvent consisting of water and a poorly water-soluble aprotic solvent, (Wherein Y, R ¹ , R ² and n have the same meanings as defined above) in a solvent layer, and then the above compound (II) in a water-insoluble aprotic solvent. , In the presence of an organic base, the formula (Wherein R ³ represents a hydrogen atom or a methyl group), and the compound represented by the formula: (In the formula, Y, R ¹ , R ² , R ³ and n have the same meanings as described above.) A method for producing an imidazole derivative.