JPH08291109A - Process for producing β-ketocarboxylic acid ester - Google Patents

Abstract

(57) [Summary] (Corrected) [Constitution] General formula 1 (R represents an alkyl group and M represents an alkali metal atom.)
After reacting the alkali metal salt of malonic acid monoalkyl ester with magnesium halide, and a base, (X is a halogen atom, n is an integer of 1 to 5, and when n is 2 or more, X may be the same or different from each other.) General formula 3 for reacting with acid fluoride (R, X and n are the same.) A method for producing a β-ketocarboxylic acid ester. [Effect] It is possible to reduce the generation of slurry in the reaction system and improve the low reproducibility of the reaction due to the non-uniformity of stirring during the reaction, to obtain the β-ketocarboxylic acid ester with high purity and high yield. Almost no consideration is given to the influence of the slurry on the durability, and it is suitable as an industrial production method of β-ketocarboxylic acid esters.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing β-ketocarboxylic acid esters useful as intermediates for agricultural chemicals and pharmaceuticals.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a β-ketocarboxylic acid ester, a potassium salt of malonic acid monoethyl ester, magnesium chloride, and triethylamine are reacted in an acetonitrile solvent, and then an acid chloride such as benzoyl chloride is reacted. A method for obtaining a β-ketocarboxylic acid ester is known [Synthesi
s), 290-292 (1993)]. However, the method using the acid chloride has a drawback that a large amount of slurry is sometimes generated and the stirring state becomes extremely poor.
By the way, when slurry is generated in the reaction system, it hinders uniform stirring of the reaction system, and in some cases only a part of the slurry is stirred, resulting in stability of the yield of the target product. Becomes extremely bad. Such instability of the yield of the target product may lead to a situation in which the intended amount of the target product cannot be obtained, which is a serious problem in the production scene on an actual industrial scale.

[0003]

An object of the present invention is to provide a method capable of producing a β-ketocarboxylic acid ester in a stable yield even when it is carried out on an industrial scale.

[0004]

As a result of various studies conducted by the inventor on a method for overcoming such drawbacks, surprisingly, when an acid fluoride was used as a raw material in place of an acid chloride, a slurry was not generated in the reaction. It was confirmed that the conventional problems caused by the generation of slurry can be solved and the above-mentioned problems can be achieved, and the present invention has been completed based on this finding.

That is, the present invention has the general formula

[0006]

[Chemical 4] (In the formula, R represents an alkyl group, and M represents an alkali metal atom.)

After reacting an alkali metal salt of malonic acid monoalkyl ester represented by: with magnesium halide and a base,

[0008]

Embedded image (In the formula, X represents a halogen atom, n represents an integer of 1 to 5, and when n is 2 or more, X may be the same or different from each other.)

A general formula characterized by reacting an acid fluoride represented by

[0010]

[Chemical 6] (In the formula, R, X and n have the same meanings as described above.)

The present invention provides a method for producing a β-ketocarboxylic acid ester represented by

The β-ketocarboxylic acid ester represented by the general formula (Formula 6) obtained by the method of the present invention includes
Although keto-enol tautomers may exist, the present invention includes any tautomers and mixtures of those tautomers. In the present specification, the structure of the compound obtained by the present invention is represented by the structure represented by the general formula (Formula 6).

The present invention will be described in detail below.

In the method of the present invention, an alkali metal salt of malonic acid monoalkyl ester (Chemical formula 4), magnesium halide and a base are reacted, and then an acid fluoride (Chemical formula 5) is further added to react them. To produce a β-ketocarboxylic acid ester (Formula 6). The generated β-ketocarboxylic acid ester (Chemical formula 6) is
It can be taken out by concentrating the organic phase by adding dilute hydrochloric acid and water to the reaction mixture obtained by the action of acid fluoride (Chemical Formula 8) to remove contaminants, and separating the organic phase. The β-ketocarboxylic acid ester (Chemical Formula 6) thus taken out can be directly used for the next use, or can be recombined or purified by distillation if desired.

In the method of the present invention, first, an alkali metal salt of malonic acid monoalkyl ester, magnesium halide and a base are reacted.

The alkali metal salt of malonic acid monoalkyl ester that can be used in this reaction may be a compound represented by the general formula (Formula 4). In the formula, as the alkyl group represented by R, an alkyl group having 1 to 4 carbon atoms, specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group can be exemplified. Are preferred, and as the alkali metal atom represented by M in the formula, for example, lithium, sodium,
Examples thereof include potassium, and among them, potassium that is industrially readily available and stable in air is preferable. Specific examples of the alkali metal salt of malonic acid monoalkyl ester having the alkyl group R and the alkali metal atom M (Formula 4) include potassium salt of malonic acid monomethyl ester, potassium salt of malonic acid monoethyl ester, and malonic acid. Monopropyl ester potassium salt, malonic acid monoisopropyl ester potassium salt, malonic acid monobutyl ester potassium salt, malonic acid monomethyl ester sodium salt, malonic acid monoethyl ester sodium salt,
Examples thereof include sodium salt of malonic acid monopropyl ester, sodium salt of malonic acid monoisopropyl ester, sodium salt of malonic acid monobutyl ester, lithium salt of malonic acid monomethyl ester and the like. In addition, these compounds are organic synthesis (Org.
Synth.) Coll. Vol. IV, 417 (1963)
It can be produced by the method described in.

Examples of magnesium halides that can be used in this reaction include anhydrous magnesium chloride and anhydrous magnesium bromide. Anhydrous magnesium chloride can be exemplified as a preferable one in view of industrial availability. The form is preferably powdery. The amount of magnesium halide used is 0. 1 with respect to 1 mol of the alkali metal salt of malonic acid monoalkyl ester (Chemical Formula 4).
It may be in the range of 5 mol to 2 mol, preferably 1.0 mol to 1.5 mol.

Examples of the base generally usable in this reaction include organic bases such as aliphatic tertiary amines, aromatic tertiary amines and nitrogen-containing heterocyclic compounds. Here, as the aliphatic tertiary amine, trialkylamines in which a fatty chain having 1 to 6 carbon atoms is substituted (for example, trimethylamine, triethylamine, tripropylamine, tributylamine, N, N-diisopropylethylamine, N, N-dimethyl) Propylamine and the like) are used as aromatic tertiary amines, and anilines (for example, N, N-dimethylaniline, N, N-) in which a C 1-6 aliphatic chain is substituted on the nitrogen atom by two.
Examples of the nitrogen-containing heterocyclic compound include diethyl aniline, etc., such as pyridines (specifically, pyridine, N, N-).
Dimethylaminopyridine, N, N-diethylaminopyridine, etc., diazines (specifically, 1,2-diazine,
1,3-diazine, 1,4-diazine and the like), triazines (specifically 1,3,4-triazine and the like), methylimidazole, hexamethylenetetramine, and 1,8
Examples thereof include nitrogen-containing heterocyclic compounds such as diazabicyclo [5.4.0] undec-7-ene (DBU). These bases may further have a substituent such as a halogen atom, an alkyl group or an alkoxy group as long as the reaction is not hindered. Industrially, the use of aliphatic tertiary amines is preferable, and for example, easily available triethylamine and the like can be mentioned as a preferable example. The amount of the base used is 1.0 mol to 6. mol per 1 mol of the alkali metal salt of malonic acid monoalkyl ester (Chemical Formula 4).
It may be 0 mol, preferably 1.0 mol to 3.0 mol.

As the solvent in this reaction, alkyl nitriles having 1 to 4 carbon atoms in the alkyl group (for example, acetonitrile, propionitrile, etc.), esters of alkyl carboxylic acid having 1 to 4 carbon atoms in the alkyl group ( For example, acetic acid esters, more specifically, for example, methyl acetate, ethyl acetate, etc.), ethers that may be chain-like or cyclic (for example, diethyl ether, diethoxymethane, 1,
2-dimethoxyethane, diglyme, tetrahydrofuran, dioxane, etc., amide bond-containing solvents (for example, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone,
N-methyl-2-pyrrolidone etc.), urea bond-containing solvents (eg tetramethylurea etc.), sulfone solvents (eg dimethyl sulfoxide, sulfolane etc.), ketones (eg acetone, methyl ethyl ketone, methyl isobutyl ketone etc.), And aromatic solvents (for example, nitrobenzene, chlorobenzene, o-dichlorobenzene, toluene, xylene, benzene, etc.) can be exemplified, and these solvents can also be used as a mixture of two or more kinds. Of these, alkyl nitriles having an alkyl group having 1 to 4 carbon atoms represented by acetonitrile, which is industrially easily available, methyl acetate, and ethyl acetate having an alkyl group represented by ethyl acetate, which has 1 to 4 carbon atoms Esters of certain alkylcarboxylic acids, ketones typified by methyl isobutyl ketone, and ethers typified by dioxane, which may be chain-like or cyclic, can be exemplified as suitable solvents. The amount of the solvent to be used is not limited as long as it can be stirred, but is usually 1 mol per mol of the alkali metal salt of malonic acid monoalkyl ester (Chemical Formula 4).
It is used in the range of L (liter) to 4 L, preferably 1.5 L to 2 L.

The reaction temperature of this reaction can be arbitrarily selected within a temperature range not higher than the boiling point of the solvent, and a range of 0 to 60 ° C. can be exemplified as a preferable reaction temperature. The reaction time of this reaction cannot be generally stated because it is influenced by the reaction conditions (for example, the type and amount of the compound or solvent used, the reaction temperature, etc.), but it is usually 2 to 8 hours. The reaction is normal pressure,
It may be carried out under pressure or reduced pressure, but it is usually carried out at normal pressure.

In the method of the present invention, the reaction solution obtained as described above is further reacted with an acid fluoride to produce the desired β-ketocarboxylic acid ester.

The acid fluoride that can be used in this reaction may be any acid fluoride represented by the general formula (Formula 5). Here, X in the formula may be a halogen atom (for example, a chlorine atom, a bromine atom, a fluorine atom, etc.), and in the case of having two or more X, X may be the same or different. May be. Such a halogen atom X
Specific examples of the acid fluoride having the formula (4) include 4-fluorobenzoyl fluoride, 2-fluorobenzoyl fluoride, 2-chloro-4,5-difluorobenzoyl fluoride, and 2,4-dichlorobenzoyl fluoride. 2,4,4-difluorobenzoyl fluoride, 3,4-difluorobenzoyl fluoride, 2,6
-Difluorobenzoyl fluoride, 2,4,5-trifluorobenzoyl fluoride, 2,4-dichloro-5
-Fluorobenzoyl fluoride, 3-chloro-4-fluorobenzoyl fluoride, 3-bromo-4-fluorobenzoyl fluoride and the like can be mentioned. The amount of the acid fluoride (formula 5) used is 0.3 mol to 1.0 mol, preferably 0.5 mol to 0.9 mol, per 1 mol of the metal salt of the malonic acid monoalkyl ester (formula 4). I wish I had it.
The acid fluoride to be used can be obtained by a known method such as a method by a Halex reaction of acid chloride or acid fluoride.

The reaction temperature of this reaction can be arbitrarily selected within a temperature range not higher than the boiling point of the solvent, but a range of 0 ° C. to 30 ° C. can be exemplified as a preferable reaction temperature. The end point of the reaction can be confirmed by, for example, high performance liquid chromatography (HPLC). The reaction time of this reaction is usually 1 hour to 2
4 hours. The method of the present invention may be carried out under any conditions of normal pressure, pressurization and reduced pressure, but it is usually carried out at normal pressure.

The desired β-ketocarboxylic acid ester (Chemical Formula 6) can be obtained from the reaction solution after the completion of this reaction by subjecting it to post-treatments such as extraction, washing, separation and concentration according to a conventional method. The β-ketocarboxylic acid ester (Chemical Formula 6) obtained here can also be used as a next reaction raw material without particular purification, and can also be distilled or appropriately selected, for example, aliphatic hydrocarbons, Halogenated hydrocarbons, alkyl ethers, acetic acid esters, alcohols, and other solvents alone or in a mixed solvent, or by reconstituting these solvents and water to form β-ketocarboxylic acid ester 6) can also be purified and isolated.

In addition, in Examples 5, 6 and 7 described later, 2,4 produced by the method of the present invention
-Methyl difluorobenzoylacetate (melting point; 43-45
C.) and methyl 2-fluorobenzoylacetate (boiling point;
96 ° C./1 mmHg) is a novel compound not described in the literature.

[0026]

INDUSTRIAL APPLICABILITY The present invention provides an industrial production method of β-ketocarboxylic acid ester. The method of the present invention is characterized in that an acid fluoride is selected and used in place of an acid chloride as an acid halide to be added to a reaction solution obtained by reacting an alkali metal salt of malonic acid monoalkyl ester, magnesium halide, and a base. It is possible to reduce the generation of slurry inside. As a result, the instability of the yield of the target product due to the generation of the slurry is improved, and the β-ketocarboxylic acid ester can be obtained with a stable yield even on an industrial scale. Furthermore, there is no need to worry about the durability of the manufacturing equipment due to the fact that a high load is applied to the stirring device due to the increased resistance during stirring, and the internal surface of the reaction vessel is abraded by the slurry, etc. Even in the scene, it is not necessary to consider the influence of the slurry. Therefore, the method of the present invention is suitable as an industrial production method of β-ketocarboxylic acid ester.

[0027]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1 20.4 g (0.12 mol) of potassium salt of malonic acid monoethyl ester and 200 ml of ethyl acetate were placed in a 1 L 4-diameter flask equipped with a stirrer, a thermometer, a reflux condenser and a calcium chloride tube. In addition, after cooling in an ice bath, 29.1 g (0.29 mol) of triethylamine and 13.7 g (0.14 mol) of anhydrous magnesium chloride were sequentially added at 10 ° C. or lower, and 35
The reaction was allowed to stir at ~ 40 ° C for 6 hours. Then, 17.8 g (0.1 mol) of 2,4,5-trifluorobenzoyl fluoride was added dropwise at 10 ° C or lower while cooling the reaction solution in an ice bath. After completion of the dropping, stirring was continued at room temperature for 12 hours for aging. Then, while cooling the reaction solution in an ice bath, 300 ml of 12% hydrochloric acid aqueous solution was added dropwise at 25 ° C or lower. Then, the mixture was transferred to a separating funnel and extracted with 200 ml of toluene. The toluene layer was washed successively with a 12% hydrochloric acid aqueous solution, water and a saturated saline solution, dried over anhydrous sodium sulfate, and the toluene was concentrated under reduced pressure to give 2,4,4. 24.1 g of ethyl 5-trifluorobenzoyl acetate was obtained [yield; 98.
0% (based on 2,4,5-trifluorobenzoyl fluoride), purity; 99.0% (HPLC analysis), melting point; 6
3 ° C to 64 ° C].

Further, the obtained 2,4,5-trifluorobenzoyl ethyl acetate was subjected to proton nuclear magnetic resonance spectrum analysis, and it was revealed that a keto tautomer and an enol tautomer were mixed. [Ethyl 2,4,5-trifluorobenzoyl acetate (mixture of keto form: enol form = 5: 5)] 60 MHz ¹ H-NMR σ value (CDCl ₃ ): 1.07 to 1.60
(m, 3H), 3.96 (d, 1H, J = 3.54Hz), 4.03 to 4.53 (m, 2H), 5.8
3 (s, 0.5H), 6.73 to 7.40 (m, 1H), 7.47 to 8.13 (m, 1H), 12.
70 (s, 0.5H)

Example 2 The procedure of Example 1 was repeated except that 200 ml of methyl acetate was used instead of 200 ml of ethyl acetate. As a result, 2,
Ethyl 4,5-trifluorobenzoyl acetate was 23.9
g was obtained [Yield: 97.0% (based on 2,4,5-trifluorobenzoyl fluoride)].

Example 3 34.0 g (0.2 mol) of potassium salt of malonic acid monoethyl ester and 200 ml of acetonitrile were added to a 1 L four-dimensional flask equipped with a stirrer, a thermometer, a reflux condenser and a calcium chloride tube. After cooling in an ice bath, 20.2 g (0.2 mol) of triethylamine and 23.8 g (0.25 mol) of anhydrous magnesium chloride were sequentially added at 10 ° C. or lower, and the mixture was stirred at room temperature for 3 hours for reaction. . Then, 17.8 g (0.1 mol) of 2,4,5-trifluorobenzoyl fluoride was added dropwise at 10 ° C or lower while cooling the reaction solution in an ice bath. After completion of the dropping, stirring was continued at room temperature for 12 hours for aging. Then, the acetonitrile was recovered under reduced pressure, 400 ml of toluene was added, and the reaction solution was cooled in an ice bath to 25
300 ml of a 12% hydrochloric acid aqueous solution was added dropwise at a temperature of not more than ° C. Then, the mixture was transferred to a separating funnel, and after separation, the toluene layer was washed with a 12% hydrochloric acid aqueous solution twice, with water twice, and with a saturated saline solution once, successively, dried over anhydrous sodium sulfate, and toluene was concentrated under reduced pressure. As a result, 22.9 g of ethyl 2,4,5-trifluorobenzoylacetate was obtained [yield: 93.0% (2,4,5-
Trifluorobenzoyl fluoride standard)].

Example 4 The reaction was carried out in the same manner as in Example 1 except that 200 ml of N, N-dimethylformamide was used instead of 200 ml of ethyl acetate, and post-treatment such as solvent recovery was carried out in the same procedure as in Example 3. It was As a result, 23.7 g of ethyl 2,4,5-trifluorobenzoylacetate was obtained [yield; 96.3% (2,
4,5-Trifluorobenzoyl fluoride standard)].

Example 5 (Production of methyl 2,4-difluorobenzoyl acetate) 20.4 g of potassium salt of malonic acid monoethyl ester
18.7 g (0.12 mol) of potassium salt of malonic acid monomethyl ester instead of (0.12 mol),
2,4,5-Trifluorobenzoyl fluoride 17.
The reaction and post-treatment were performed in the same manner as in Example 1 except that 13.8 g (0.086 mol) of 2,4-difluorobenzoyl fluoride was used instead of 8 g (0.1 mol). As a result, 18.0 g of methyl 2,4-difluorobenzoylacetate as white crystals was obtained [yield; 97.8%
(2,4-difluorobenzoyl fluoride standard), purity; 97.3% (HPLC analysis)].

(Physical properties of methyl 2,4-difluorobenzoylacetate) Melting point: 43 to 45 ° C. Boiling point: 92 ° C./0.8 mmHg (confirmation data) [(mixture of keto form: enol form = 6: 4)] 60 MHz ¹ H-NMR σ value (CDCl ₃ ): 3.78 (s, 1.8
H), 3.97 (m, 2.4H), 5.80 (s, 0.4H), 6.60 ~ 7.40 (m, 2H),
7.61 ~ 8.30 (m, 1H), 12.60 (s, 0.4H) IR (KBr tablet, cm ^-1 ): 3200 ~ 2700, 1740, 1690, 1600,
1510, 1440, 1410, 1330, 1270, 1210, 1155, 1102

Example 6 The reaction temperature of malonic acid monomethyl ester potassium salt with triethylamine and anhydrous magnesium chloride was adjusted to 3
It carried out like Example 5 except having changed from 5-40 ° C to room temperature. As a result, 17.5 g of methyl 2,4-difluorobenzoyl acetate was obtained [yield; 95.2% (2,4-
Difluorobenzoyl fluoride standard)].

Example 7 (Production of methyl 2-fluorobenzoylacetate) 2 instead of 2,4-difluorobenzoylfluoride
-Fluorobenzoyl fluoride 12.2 g (0.08
Example 5 was repeated except that 6 mol) was used. As a result, 16.0 g of methyl 2-fluorobenzoylacetate was obtained as a colorless transparent liquid [yield; 95.1% (2-fluorobenzoyl fluoride standard), purity: 96% (HP
LC analysis)].

[Physical properties of methyl 2-fluorobenzoylacetate (mixture of keto form: enol form = 8: 2)] Boiling point: 96 ° C./1.0 mmHg 60 MHz ¹ H-NMR σ value (CDCl ₃ ): 3.75 ( s, 3H),
4.01 (d, 1.6H, J = 3.54Hz), 5.83 (s, 0.2H), 6.87 ~ 8.12 (m, 4
H), 12.57 (s, 0.2H) IR (NaCl plate, cm ^-1 ): 3300 to 2700, 1744, 1690, 1610, 14
80, 1452, 1440, 1400, 1332, 1260, 1203, 1150, 1105

Examples 8 to 12 Examples 8 to 12 were carried out by substituting the type of the alkali metal salt of acid fluoride or malonic acid monoalkyl ester used in each of the examples (Table 1) (the number of moles used was the same). In the same manner as in Example 1 and in Example 12 in the same manner as in Example 5 to obtain corresponding products (β-ketocarboxylic acid ester). The results are shown in (Table 1).

[0039]

[Table 1]

Example 13 200 ml of dioxane instead of 200 ml of acetonitrile
The same procedure as in Example 3 was performed except that was used. as a result,
2 ethyl 2,4,5-trifluorobenzoyl acetate
3.4 g was obtained [yield; 95.0% (based on 2,4,5-trifluorobenzoyl fluoride)].

Claims (1)

[Claims] 1. A general formula: (In the formula, R represents an alkyl group and M represents an alkali metal atom.) After reacting an alkali metal salt of a malonic acid monoalkyl ester represented by the formula: magnesium halide, and a base, the following general formula: Chemical 2] (In the formula, X represents a halogen atom, n represents an integer of 1 to 5, and when n is 2 or more, X may be the same or different from each other.) Which is characterized by the general formula: (In the formula, R, X and n have the same meanings as described above.) A method for producing a β-ketocarboxylic acid ester.