JP2540390B2 - Method for producing β-keto ester - 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 .beta.-ketoester useful as a raw material for producing medical and agricultural chemicals.

[0002]

Description of the Prior Art The following are known methods for producing β-ketoesters, which have been considered to be industrially useful.

A process for producing alkynyl acetoacetic acid ester by deacetylation reaction using various bases. (J. Am. Chem. Soc., 67.
Vol., 2197, 1945), (Ceskoslo
v. Farm. , 35, 162, 1986),
(Helvetica Chimica Acta, 3
5: 2280, 1952), JP-A-1-1932
No. 42 publication.

A method for producing using Meldrum's acid. JP-A-54-106421, (J. Org. Che
m. , 43, 2084, 1978).

A method for producing using a malonic acid half ester. (J. Am. Chem. Soc., Vol. 66, 1
286, 1944).

[0006] A method for producing by reacting an alkyl halide with a dianion of acetoacetic acid ester. (J. Am. Chem. Soc., Vol. 92, 670.
2 pages, 1970).

A method for producing a β-ketoester by reacting a diazoacetic acid ester with an aldehyde in the presence of a catalytic amount of a Lewis acid. (J. Org. Chem., 54
Vol. 3, pp. 3258, 1989).

However, each of the above items 1 to 3 has the following problems. In the above method, a large amount of acetoacetic acid ester is by-produced when the target compound β-ketoester is obtained, and therefore it must be purified. Also,
When the physical properties of the by-product and the target compound are similar to each other, it is difficult to obtain a high-purity target compound.

According to the methods (1) and (2), raw materials such as meldrum acid, malonic acid half ester, and dianion of acetoacetic acid ester are expensive. Therefore, it is necessary to use raw materials more suitable for industrial production.

In the method (1), the target compound can be prepared by reacting the diazoacetic acid ester with an alkylaldehyde in the presence of a catalytic amount of stannous chloride, but the diazoacetic acid ester used is active and easily decomposed. Moreover, an isomer that is difficult to remove is produced as a by-product. Therefore, it is necessary to suppress the decomposition of the diazoacetic acid ester which is a manufacturing raw material and the by-product of the isomer of the target compound.

Therefore, from the above-mentioned problems, it has been desired to develop a method capable of using a cheaper raw material than ever before and easily industrially producing a target compound in a high yield.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel method for producing β-ketoester which is useful as a raw material for producing agricultural chemicals.

[0013]

DISCLOSURE OF THE INVENTION As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that diazo compounds are present in the presence of a catalytic amount of stannous chloride and a catalytic amount of an alkoxydialkylsulfonium salt. By reacting ethyl acetate with propionaldehyde, it is possible to suppress the decomposition of diazoacetic acid ester and the by-product of the isomer of the target compound, and to find a novel method capable of producing the target compound in high yield, the present invention Has been completed.

That is, the present invention provides a compound A of the following formula:

[0015]

Embedded image

(Wherein R ¹ represents an alkyl group) and a compound B of the following formula:

[0017]

[Chemical 6]

(Wherein R ² represents an alkyl group) and a diazoacetic acid ester, a catalytic amount of stannous chloride and a catalytic amount of a compound C of the following formula:

[0019]

[Chemical 7]

(In the formula, X represents a counter anion; R ³ and R ⁴ represent alkyl groups which may be different from each other.)
Compound D of the following formula characterized by reacting in the presence of an alkoxydialkylsulfonium salt represented by:

[0021]

Embedded image

The present invention relates to a method for producing a β-ketoester represented by the formula (wherein R ¹ and R ² are as defined above).

The present invention will be described in detail below. Β-ketoester (compound D), which is the above-mentioned target compound,
Alkyl aldehyde (compound A), which is the raw material for its production,
Diazoacetic acid ester (Compound B) and alkoxydialkyl sulfonium salt (Compound C) which is a production catalyst thereof
In, R ¹ , R ² , R ³ , R ⁴ and X are as follows.

R ¹ may be a linear or branched alkyl group; preferably a linear or branched alkyl group having 1 to 10 carbon atoms; more preferably linear. A lower alkyl group of the formula: more preferably an ethyl group.

R ² may be a linear or branched alkyl group; preferably a linear or branched lower alkyl group; and more preferably a linear lower alkyl group. Well; more preferably an ethyl group.

Examples of X include a counter anion [eg, a halogen atom (chlorine atom, bromine atom, fluorine atom, iodine atom, etc.), ClO ₄ , BF ₄ , PF ₆ etc.]; preferably a halogen atom Chlorine atom is more preferable.

Examples of R ³ and R ⁴ include linear or branched alkyl groups which may be different from each other; preferably linear or branched lower alkyl groups; more preferably Is preferably a linear lower alkyl group; more preferably a methyl group or an ethyl group.

In the synthesis of compound D (β-keto ester which is the target compound), as shown below, compound A (alkyl aldehyde) which is a raw material and compound B (diazoacetic acid ester) are usually used in catalytic amounts. (Alkoxydialkyl sulfonium salt) and a catalytic amount of stannous chloride.

[0029]

[Chemical 9]

(In the formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as described above.) The solvent is not particularly limited as long as it does not directly participate in this reaction, and various solvents can be used. Chlorinated solvents such as benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, methylene chloride, chloroform, dichloromethane, dichloroethane, trichloroethylene, cyclohexane, acetonitrile Or non-aromatic, aliphatic, alicyclic hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like;
A mixture of the above-mentioned solvents can be used), but it is preferable to use dichloromethane which can accelerate the reaction rate and is economically advantageous.

The amount of the solvent used is the amount of compound B
The (diazoacetate) can be used in a concentration range of 2 to 50% by weight, but it is preferable to use the compound B in a concentration of 5 to 20% by weight. .

The compound A (alkyl aldehyde) can be usually used in an excess amount with respect to the compound B, but it is preferable to use it in a 1.0 to 5.0-fold molar amount, and more preferable. Is preferably used in a 1.1 to 1.8-fold molar amount.

The stannous chloride may be used in an amount of 0.1 to 30% by weight based on the compound B, preferably 0.5 to 10% by weight, more preferably 0.5 to 10% by weight. Is preferably used at 3 to 7% by weight.

The amount of compound C used is 1 with respect to compound B.
Can be used in an amount of up to 20% by weight, preferably 2
~ 15% by weight, preferably 8
It is recommended to use ~ 12% by weight.

The reaction temperature is -50 to 100 ° C,
The temperature is preferably −20 to 80 ° C., more preferably −
10-30 degreeC is good. The reaction time varies depending on the above-mentioned concentration and temperature, but the reaction can be terminated by stirring for 20 minutes after the generation of nitrogen is stopped, and is usually 0.5 to 4 hours.

The raw materials and the catalyst are mixed by adding the compound A dropwise to a solution containing the compound B, a catalytic amount of stannous chloride and the catalytic amount of the compound C, or by mixing the compound A, the compound B and the catalytic amount of the compound C. Can be carried out by adding a catalytic amount of stannous chloride to the solution consisting of

As the compound A, a commercially available product can be used. Examples of the compound A include propionaldehyde, n-butyraldehyde, isobutyraldehyde, n-valeraldehyde, isovaleraldehyde, pivalaldehyde,
n-capronaldehyde, isocapronaldehyde, n
-Heptyl aldehyde and the like can be mentioned.

The compound B can be obtained, for example, from Org. Synt
h. Vol. 3, p. 392 (1955), Org. Syn
th. , Vol. 4, p. 424 (1963), etc., and can be easily produced. Examples of the compound B include methyl diazoacetate, ethyl diazoacetate, propyl diazoacetate, isopropyl diazoacetate, butyl diazoacetate, isobutyl diazoacetate, amyl diazoacetate, isoamyl diazoacetate and the like.

Compound C is described, for example, in Bull. Che
m. Soc. Jpn. , 53, 1469 (1980
It can be easily produced according to the method described in (1).

Examples of the compound C include, for example, methoxydimethylsulfonium iodide, methoxydimethylsulfonium bromide, methoxydimethylsulfonium chloride, ethoxydimethylsulfonium iodide, ethoxydimethylsulfonium bromide, ethoxydimethylsulfur. Phonium chloride, methoxydiethylsulfonium iodide, methoxydiethylsulfonium bromide, methoxydiethylsulfonium chloride, ethoxydiethylsulfonium iodide, ethoxydiethylsulfonium bromide, ethoxydiethylsulfonium chloride, etc. be able to.

The desired compound D produced as described above can be obtained by washing with water as it is after completion of the reaction to remove stannous chloride and compound C and concentrating, and further, if necessary. It can be highly purified by known means such as distillation purification and various chromatography.

The compound D corresponds to the above-mentioned compounds A and B, for example, methyl propionyl acetate,
Ethyl propionyl acetate, propyl propionyl acetate,
Isopropyl propionyl acetate, butyl propionyl acetate, isobutyl propionyl acetate, amyl propionyl acetate, isoamyl propionyl acetate, ethyl butyryl acetate, ethyl isobutyryl acetate, ethyl valeryl acetate, isovaleryl acetate, ethyl pivaloyl acetate, ethyl caproyl acetate, ethyl isocaproyl acetate, heptanoyl Examples thereof include ethyl acetate.

[0043]

EXAMPLES The present invention will be specifically described below with reference to Examples and Comparative Examples. It should be noted that these examples do not limit the scope of the present invention.

Example 1 Ethyl diazoacetate (1.
00g, 8.77mmol) and methoxydimethylsulfonium iodide (0.1g) were added, and propionaldehyde (0.56g, 9.65mmo was added under stirring.
l) was added dropwise. This was stirred at room temperature for 30 minutes, stannous chloride (50 mg) was added, and the mixture was stirred at room temperature for 1 hour.
The produced ethyl propionyl acetate was quantified by gas chromatography and as a result, the target compound was 1.14 g (yield 90%).

Reference Example 1 Ethyl diazoacetate (1.
00g, 8.77mmol), stannous chloride (50m
g) was added, and propionaldehyde (0.58
(g, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. As a result of quantifying the produced ethyl propionyl acetate by gas chromatography, the target compound was 0.92 g.
(Yield 72%).

Reference Example 2 Ethyl diazoacetate (1.
00 g, 8.77 mmol) and boron trifluoride ether complex (3 drops) were added thereto, and propionaldehyde (0.58 g, 1.00 mmol) was added dropwise under stirring, followed by stirring at room temperature for 1 hour. As a result of quantifying the produced ethyl propionyl acetate by gas chromatography, the target compound was 0.78 g (yield 62%).

Reference Example 3 Water (6 ml) was added to glycine ethyl ester hydrochloride (4.1
9 g, 30 mmol) was dissolved and dichloromethane (18 ml) was added thereto. A solution prepared by adding sodium nitrite (2.5 g) to water (6 ml) was added dropwise to the above solution cooled to -5 ° C, and further cooled to -10 ° C to prepare a 5 wt% sulfuric acid aqueous solution (3 g). It was dripped slowly. After that, the refrigerant was removed, and the temperature was slowly raised to room temperature to separate the organic layer.
l) was added and extracted to separate the organic layer. The obtained organic layers were combined, and stannous chloride (50 mg) was added thereto-
Cool to 10 ° C. and, under stirring, propionaldehyde (1.
91 g, 33.0 mmol) was added dropwise. This was stirred at 0 ° C. for 2 hours and then at room temperature for 2 hours. As a result of quantifying the produced ethyl propionyl acetate by gas chromatography, the target compound was 3.11 g (yield 72%).

[0048]

EFFECTS OF THE INVENTION According to the novel production method of the present invention, the decomposition of raw material compounds and the generation of by-products can be suppressed, and β-ketoester useful as a raw material for producing pharmaceuticals and agricultural chemicals can be produced in high yield.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location // C07B 61/00 300 C07B 61/00 300

Claims (1)

(57) [Claims] 1. The following formula: (In the formula, R ¹ represents an alkyl group.) And an alkyl aldehyde represented by the following formula: (In the formula, R ² represents an alkyl group.), A diazoacetic acid ester represented by the formula: and a catalytic amount of stannous chloride and a catalytic amount of the following formula: (Wherein, X represents a counter anion; R ³ and R ⁴ represent alkyl groups which may be different from each other), and the reaction is carried out in the presence of an alkoxydialkylsulfonium salt. Formula: (Wherein, R ¹ and R ² are as defined as described in the.) Beta-ketoester method for manufacturing indicated by.