JP2540391B2 - Process for producing β-ketoester - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing β-ketoester useful as a raw material for producing pharmaceuticals 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, 2087, 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 alkylaldehyde in the presence of a catalytic amount of a Lewis acid. (J. Org. Che
m. , 54, p. 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 process for producing β-ketoester which is useful as a raw material for producing medical and agricultural chemicals.

[0013]

DISCLOSURE OF THE INVENTION As a result of intensive studies for solving the above-mentioned problems, the present inventors have found that diazoacetic acid ester is present in the presence of a catalytic amount of stannous chloride and a catalytic amount of a triarylmethyl salt. The present invention has been completed by discovering a novel method capable of suppressing the decomposition of diazoacetic acid ester and the by-product of the isomer of the target compound by reacting the target compound with an alkyl aldehyde, and producing the target compound in a high yield, thus completing the present invention. Came to do.

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

[0015]

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(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]

(Wherein X represents a counter anion; Ar represents a phenyl group which may have a substituent), and the reaction is carried out in the presence of a triarylmethyl salt. Compound of formula D:

[0021]

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(Wherein R ¹ and R ² have the same meanings as described above) and relates to a process for producing a β-ketoester.

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,
In the diazoacetic acid ester (compound B) and its production catalyst triarylmethyl salt (compound C), R ¹ ,
R ² , X and Ar are as shown below.

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 Ar include a phenyl group which may have a substituent (eg, a linear or branched alkyl group).

The synthesis of compound D (the target compound β-ketoester) is usually carried out by mixing the starting compound A (alkyl aldehyde) and compound B (diazoacetate) with a catalytic amount of compound C, as shown below. It can be carried out by reacting in the presence of (triarylmethyl salt) and a catalytic amount of stannous chloride.

[0029]

[Chemical 9]

(In the formula, R ¹ , R ² , X and Ar 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 (eg, Chlorinated or not, such as, benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, methylene chloride, chloroform, dichloromethane, dichloroethane, trichloroethylene, acetonitrile, cyclohexane Aromatic, aliphatic, alicyclic hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; mixtures of the above solvents, etc.) can be used. Is economically advantageous because it can accelerate It is preferable to use methane

The amount of the solvent used is the amount of compound B
The (diazoacetate) may 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, more preferably 3
It is recommended to use ~ 7% 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 usually 0.5 to 4 hours. is there.

The raw material and the catalyst are mixed by dropping compound A into a solution containing compound B, a catalytic amount of stannous chloride and a catalytic amount of compound C, or by mixing compound A, compound B and a catalytic amount of compound. This can be done by adding a catalytic amount of stannous chloride to the solution of C.

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 Chem. Be
r. 92, 83 (1959), J. Chem.
Soc. , Page 2773 (1959), etc., for easy production.

Examples of the compound C include trityl chloride (triphenylmethyl chloride), trityl bromide, trityl iodide, trityl perchlorate, trityl tetrafluoroborate, trityl hexafluorophosphate and the like.

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

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 acetate Examples thereof include ethyl.

[0045]

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 Dichloroacetate (1..ml) was added to dichloromethane (14 ml).
43 g, 12.5 mmol) and trityl chloride (0.1 g) were added, and propionaldehyde (0.81 g, 14.0 mmol) was added dropwise with stirring. This was stirred at room temperature for 2 hours, stannous chloride (50 mg) was added, 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 1.67 g (yield 93%).

Example 2 Dichloroacetate (1.0 ml) was added to dichloromethane (10 ml).
00g, 8.77mmol), trityl chloride (5
0 mg) and stannous chloride (50 mg) were added, the mixture was cooled to 5 ° C. or lower, and propionaldehyde (0.56) was added under stirring.
g, 9.65 mmol) was added dropwise. This was stirred at 5 ° 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 1.20 g (yield: 95%).

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, trityl chloride (50 mg) and stannous chloride (50 mg) were added thereto, the mixture was cooled to 5 ° C or lower, and propionaldehyde (1.91 g, 33.0 m was stirred.
(mol) was added dropwise. This was stirred at 5 ° 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 3.76 g (yield: 87).
%).

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.
00g, 8.77mm0l), boron trifluoride ether complex (3 drops), propionaldehyde (0.58g, 1.00mmol) was added dropwise under stirring, and then 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 0.78 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.
1) 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%).

[0052]

EFFECTS OF THE INVENTION According to the novel process 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.

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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; Ar represents a phenyl group which may have a substituent), and the reaction is carried out in the presence of a triarylmethyl salt. Chemical 4] (Wherein, R ¹ and R ² are as defined as described in the.) Beta-keto ester of formula represented by.