JPH04270241A - Production of beta-ketoester - Google Patents

Abstract

PURPOSE:To provide a new excellent method for production of beta-ketoesters useful as a raw material for production of medical and agricultural drugs. CONSTITUTION:A new method for production of beta-ketoesters characterized by a reaction of a diazoacetate such as ethyl diazoacetate with an alkyl aldehyde such as propyl aldehyde in the presence of a catalytic amount of stannous chloride and a catalytic amount of an alkoxydialkylsulfonium salt such as methoxydimethylsulfonium iodide. Decomposition of the raw material compounds and generation of by-products can be inhibited and the objective beta-ketoesters useful as a raw material compound for production of medical and agricultural drugs can be produced in a high yield.

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 β-ketoester useful as a raw material for producing pharmaceuticals and agrochemicals.

0002

[Description of the Prior Art] Conventionally, the following methods are known as methods for producing β-ketoesters which are considered to be industrially useful.

(2) A method for producing alkynyl acetoacetate by deacetylation using various bases. (J. Am. Chem. Soc., vol. 67, p. 2197, 1945), (Ceskoslov.
Farm. , vol. 35, p. 162, 1986), (He
lvetica Chimica Acta, 35
Volume, 2280 pages, 1952), JP-A-1-19324
It is described in Publication No. 2.

[0004] ■Production method using Meldrum's acid. JP-A-54-106421, (J.Org.Che
m. , Vol. 43, p. 2084, 1978).

[0005] ■Production method using malonic acid half ester. (J. Am. Chem. Soc., Vol. 66, 1
286, 1944).

(2) A method for producing by reacting an alkyl halide with a dianion of acetoacetate. (J. Am. Chem. Soc., vol. 92, 6702
Page, 1970).

(2) A method for producing a β-ketoester by reacting a diazoacetate with an aldehyde in the presence of a catalytic amount of a Lewis acid. (J. Org. Chem., vol. 54, p. 3258, 1989).

However, these methods (1) to (4) have various problems as shown below. In method (2), a large amount of acetoacetate is produced as a by-product when obtaining the target compound, .beta.-ketoester, and therefore must be purified. Also,
When the physical properties of the by-product and the target compound are similar, it is difficult to obtain the target compound with high purity.

[0009] In methods (1), (2), and (2), the raw materials such as Meldrum's acid, malonic acid half ester, and acetoacetate dianion are expensive. Therefore, it is necessary to use raw materials that are more suitable for industrial production.

[0010] In method (2), the target compound can be produced by reacting diazoacetate with an alkyl aldehyde in the presence of a catalytic amount of stannous chloride, but because the diazoacetate used is active, it does not decompose. It produces by-product isomers that are easy to remove and difficult to remove. Therefore, it is necessary to suppress the decomposition of the diazoacetic acid ester, which is a raw material for production, and the by-production of isomers of the target compound.

[0011] Therefore, in view of the above-mentioned problems, it has been desired to develop a method that can use manufacturing raw materials that are cheaper than conventional ones and that can easily industrially produce the target compound in high yield.

0012

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel method for producing β-ketoesters useful as raw materials for producing pharmaceuticals and agricultural chemicals.

[0013]

[Means for Solving the Problems] As a result of intensive research to solve the above-mentioned problems, the present inventors have discovered that diazo- We have discovered a new method that can suppress the decomposition of diazoacetate and the by-production of isomers of the target compound by reacting ethyl acetate and propionaldehyde, and can produce the target compound in high yield, and the present invention I was able to complete it.

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

00
15]

[C5]

An alkyl aldehyde represented by the formula (wherein R1 represents an alkyl group) and a compound B of the following formula:

001
7]

[C6]

A diazoacetic ester represented by the formula (wherein R2 represents an alkyl group) is mixed with a catalytic amount of stannous chloride and a catalytic amount of a compound C of the following formula:

[0019]

[C7]

(In the formula, X represents a counter anion; R3 and R4 represent an alkyl group which may be different from each other.)
Compound D of the following formula, characterized in that it is reacted in the presence of an alkoxydialkylsulfonium salt represented by:

[
0021

[Chemical formula 8]

The present invention relates to a method for producing a β-ketoester represented by the formula (wherein R1 and R2 have the same meanings as described above).

The present invention will be explained in detail below. β-ketoester (compound D), which is the target compound,
Alkyl aldehyde (compound A), which is the raw material for its production,
Diazoacetic acid ester (compound B) and its production catalyst alkoxydialkylsulfonium salt (compound C)
In, R1, R2, R3, R4 and X are as follows.

[0024] As R1, straight-chain or branched alkyl groups can be mentioned; preferably straight-chain or branched alkyl groups having 1 to 10 carbon atoms; more preferably straight-chain is preferably a lower alkyl group; more preferably an ethyl group.

Examples of R2 include linear or branched alkyl groups; preferably linear or branched lower alkyl groups; more preferably linear lower alkyl groups. ; Ethyl group is more preferred.

Examples of X include counteranions such as halogen atoms (chlorine atom, bromine atom, fluorine atom, iodine atom, etc.), ClO4, BF4, PF6, etc.; preferably, a halogen atom; More preferably, a chlorine atom is used.

Examples of R3 and R4 include straight-chain or branched alkyl groups which may be different from each other; preferably straight-chain or branched lower alkyl groups; more preferably straight-chain or branched lower alkyl groups; Chain-like lower alkyl groups are preferred; methyl and ethyl groups are more preferred.

The synthesis of Compound D (β-ketoester, which is the target compound) is usually carried out by mixing starting materials Compound A (alkyl aldehyde) and Compound B (diazoacetate) with a catalytic amount of Compound C ( alkoxydialkylsulfonium salt) and a catalytic amount of stannous chloride.

[0029]

[Chemical formula 9]

(In the formula, R1, R2, R3, R4 and Chlorinated or not, such as benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, methylene chloride, chloroform, dichloromethane, dichloroethane, trichlorethylene, cyclohexane, acetonitrile Aromatic, aliphatic, and cycloaliphatic hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.;
Although mixtures of the above-mentioned solvents can be used, it is preferable to use dichloromethane because it can accelerate the reaction rate and is economically advantageous.

[0031] The amount of the solvent used is determined by the amount of the solvent used for compound B (
Diazoacetic ester) can be used so that the concentration ranges from 2 to 50% by weight, but it is preferably used so that the concentration of compound B is from 5 to 20% by weight.

Compound A (alkyl aldehyde) can be used in an amount usually in excess of Compound B, but is preferably used in an amount of 1.0 to 5.0 times the molar amount, and more preferably is preferably used in a molar amount of 1.1 to 1.8 times.

The amount of stannous chloride to be used can be 0.1 to 30% by weight, preferably 0.5 to 10% by weight, and more preferably 0.5 to 10% by weight. is preferably used in an amount of 3 to 7% by weight.

The amount of compound C to be used is 1 to compound B.
It can be used at ~20% by weight, but preferably 2
It is preferable to use it in an amount of ~15% by weight, more preferably 8% by weight.
It is preferable to use it in an amount of ~12% by weight.

[0035] The reaction temperature is -50 to 100°C,
Preferably -20 to 80°C, more preferably -
The temperature is preferably 10 to 30°C. The reaction time varies depending on the above-mentioned concentration and temperature, but the reaction can be completed by stirring for an additional 20 minutes after nitrogen is no longer generated, and is usually 0.5 to 4 hours.

The method of mixing the raw materials and the catalyst is to drop Compound A into a solution consisting of Compound B, a catalytic amount of stannous chloride, and a catalytic amount of Compound C, or to mix Compound A, Compound B, and a catalytic amount of Compound C. This can be done by adding a catalytic amount of stannous chloride to a solution consisting of:

[0037] Compound A can be a commercially available product. Compound A includes propionaldehyde, n-butyraldehyde, isobutyraldehyde, n-valeraldehyde, isovaleraldehyde, pivalaldehyde, n-valeraldehyde,
-Capronaldehyde, Isocaproaldehyde, n-
Examples include heptylaldehyde.

Compound B can be obtained, for example, from Org. Synth
．． , vol. 3, p. 392 (1955), Org. Synt
h. , Vol. 4, p. 424 (1963). Compound B includes, for example, methyl diazoacetate, ethyl diazoacetate,
Examples include propyl diazo acetate, isopropyl diazo acetate, butyl diazo acetate, isobutyl diazo acetate, amyl diazo acetate, and isoamyl diazo acetate.

Compound C can be prepared, for example, by Bull. Chem
．． Soc. Jpn. , Vol. 53, p. 1469 (1980).

Examples of compound C include methoxydimethylsulfonium iodide, methoxydimethylsulfonium bromide, methoxydimethylsulfonium chloride, ethoxydimethylsulfonium iodide, ethoxydimethylsulfonium bromide, and ethoxydimethylsulfonium bromide. Examples include phonium chloride, methoxydiethylsulfonium iodide, methoxydiethylsulfonium bromide, methoxydiethylsulfonium chloride, ethoxydiethylsulfonium iodide, ethoxydiethylsulfonium bromide, ethoxydiethylsulfonium chloride, etc. be able to.

The target compound D produced as described above can be obtained by directly washing with water to remove stannous chloride and compound C after the reaction is completed, and then concentrating. Depending on the situation, it can be made highly pure by known means such as distillation purification and various chromatography methods.

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

[0043]

[Examples] The present invention will be specifically explained below with reference to Examples and Comparative Examples. Note that these Examples do not limit the scope of the present invention.

Example 1 Ethyl diazoacetate (1.
00g, 8.77mmol), methoxydimethylsulfonium iodide (0.1g) and propionaldehyde (0.56g, 9.65mmol) were added under stirring.
) was added dropwise. This was stirred at room temperature for 30 minutes, then stannous chloride (50 mg) was added and stirred at room temperature for 1 hour. As a result of quantifying the produced ethyl propionylacetate by gas chromatography, the amount of the target compound was 1.14 g (yield: 90%).

Reference Example 1 Ethyl diazoacetate (1.
00g, 8.77mmol), stannous chloride (50mg
) and propionaldehyde (0.58g) under stirring.
, 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 propionylacetate by gas chromatography, the amount of 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 propionylacetate by gas chromatography, the amount of the target compound was 0.78 g (yield: 62%).

Reference Example 3 Glycine ethyl ester hydrochloride (4.1
9 g, 30 mmol) was dissolved, and dichloromethane (18 ml) was added thereto. A solution of sodium nitrite (2.5 g) in water (6 ml) was added dropwise to the above solution cooled to -5°C, and further cooled to -10°C, a 5% by weight sulfuric acid aqueous solution (3 g) was added. It dripped slowly. After that, the refrigerant was removed and the temperature was slowly raised to room temperature to separate the organic layer, and this aqueous layer was further added with dichloromethane (12 m
l) was added and extracted to separate the organic layer. The obtained organic layers were combined, stannous chloride (50 mg) was added thereto, and -
Cool to 10°C and add propionaldehyde (1.
91 g, 33.0 mmol) was added dropwise. This was stirred at 0° C. for 2 hours, and then further stirred at room temperature for 2 hours. As a result of quantifying the produced ethyl propionyl acetate by gas chromatography, the amount of the target compound was 3.11 g (
Yield: 72%).

[0048]

According to the novel production method of the present invention, it is possible to suppress the decomposition of raw material compounds and the generation of by-products, and to produce β-ketoesters useful as raw materials for the production of pharmaceuticals and agricultural chemicals in high yields.

Claims (1)

[Claims] Claim 1: An alkyl aldehyde represented by the following formula: [Formula 1] (wherein, R1 represents an alkyl group) and an alkyl aldehyde represented by the following formula: [Formula 2] (wherein, R2 represents an alkyl group). A catalytic amount of stannous chloride and a catalytic amount of stannous chloride and a catalytic amount of the following formula: [Formula 3] (wherein, The reaction is carried out in the presence of an alkoxydialkylsulfonium salt represented by the following formula: (wherein R1 and R2 are as defined above) Method for producing β-ketoester.