JP2000355588A - Production of alfa-acetyl-gamma-butyrolactone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing α-acetyl-γ-butyrolactone under mild conditions. SOLUTION: An acetoacetic ester (methyl acetoacetate) is allowed to react with ethylene oxide in the presence of an alkali metal component (sodium hydroxide or the like) in an alcohol, for example, methanol, then alcohols are distilled off, until the methanol concentration remaining in the reaction mixture is lowered to 1-20 wt.%, and the residue is neutralized with an aqueous sulfuric acid in a temperature range of from 10 deg.C to 30 deg.C, phase-separated and the objective α-acetyl-γ-butyrolactone is collected from the organic layer. The amount of the alkali metal component used is about 0.7-1.1 equivalent based on the acetoacetic ester.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing industrially useful α-acetyl-γ-butyrolactone, which is used as an intermediate for pharmaceuticals such as vitamin B1 and organic industrial chemicals.

[0002]

2. Description of the Related Art As a method for obtaining α-acetyl-γ-butyrolactone, for example, γ-butyrolactone and acetic acid ester are dissolved in an alcohol solvent in the presence of an alkali component such as an alkali alcoholate, an alkali metal or a hydroxide thereof. A method of reacting and neutralizing the reaction mixture with acetic acid is known (Japanese Patent Publication No. 31-8271). However, according to this method, it is difficult for the neutralized solution to separate into an aqueous layer containing a large amount of an organic acid salt such as sodium acetate and an organic layer mainly containing acetylbutyrolactone, and the separation property is poor. Also,
Since the dissolution loss of the organic substance in the aqueous layer is large, the yield decreases. Acetic acid is an expensive acid for industrial use, and it is difficult to produce α-acetyl-γ-butyrolactone at low production cost.

On the other hand, Japanese Patent Publication No. 42-12662 discloses that acetoacetate and ethylene oxide are reacted in the presence of at least one equivalent (based on acetoacetate) of an alkali component, and methanol is distilled from the reaction mixture under reduced pressure. It is described that α-acetyl-γ-butyrolactone can be obtained at a yield of 76% by neutralizing at 30 to 50 ° C. with a 13 to 25% by weight aqueous sulfuric acid solution after leaving. It is also stated that the methanol distillation may be performed after the neutralization treatment. This document also describes that it is useful to use sulfuric acid instead of acetic acid under special conditions from the viewpoints of dissociation constant, reduction of dissolution loss, cost, and the like. Further, this document describes that it is necessary to limit the temperature range in order not to precipitate a solid phase (such as sodium sulfate). However, this method also degrades 24% of the expensive methyl acetoacetate. For this reason, it is difficult to produce α-acetyl-γ-butyrolactone at low production cost.

[0004]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for producing .alpha.-acetyl-.gamma.-butyrolactone with high efficiency under mild conditions.

Another object of the present invention is to provide α-acetyl-γ-
An object of the present invention is to provide a method for producing butyrolactone at a low production cost.

Another object of the present invention is to provide a method for producing α-acetyl-γ-butyrolactone in high yield.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, before neutralizing the reaction mixture with sulfuric acid, the alcohol concentration in the reaction mixture was previously concentrated by concentration. If adjusted to a specific concentration, neutralization can be performed without depositing a solid phase even under relatively low temperature and mild conditions. Even if the neutralization is performed at a low temperature, high layer separation between the aqueous layer and the organic layer can be achieved. Can be maintained, and α
The present inventors have found that the extraction efficiency and yield of -acetyl-γ-butyrolactone are improved, and completed the present invention.

That is, in the process for producing α-acetyl-γ-butyrolactone according to the present invention, a residual alcohol concentration of 0 is obtained from a reaction mixture obtained by reacting acetoacetic ester and ethylene oxide in an alcohol in the presence of an alkali metal component. The alcohol is distilled off until the concentration becomes 0.1 to 20% by weight, neutralized with a sulfuric acid aqueous solution at a temperature of 10 ° C. or more and less than 30 ° C., and the layers are separated to obtain α-acetyl-γ-butyrolactone from the organic layer. The step of reacting the acetoacetic ester with ethylene oxide, the step of distilling off the alcohol, and the step of neutralization may be performed at a temperature of about 10 to 28 ° C. The alkali metal component may be about 0.7 to 1.1 equivalents to the acetoacetate ester. Acetoacetate, for example,
It is a C _1-4 alkyl acetoacetate. Further, α-acetyl-γ-butyrolactone may be further extracted from the aqueous layer after layer separation.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION [Reaction Step] In the present invention, acetoacetic ester and ethylene oxide are mixed in an alcohol solvent.
The reaction is performed in the presence of an alkali metal component.

As the acetoacetate, C _1-4 alkyl acetoacetate such as methyl acetoacetate, ethyl acetoacetate, butyl acetoacetate and butyl acetoacetate can be used. The preferred acetoacetate is methyl acetoacetate.

The proportion of ethylene oxide is, for example, about 1 to 3 mol, preferably about 1 to 2 mol, and more preferably about 1.3 to 1.7 mol, per 1 mol of acetoacetate.

As the alkali metal component, sodium,
Alkali metals such as potassium, their hydroxides, or
These alcoholates (such as methylate and ethylate)
C_{1- Four}Alcoholate, etc.). In addition,
The rucolate is, for example, an alkali metal or a hydroxide thereof.
Is a component produced in the system from
There may be. The preferred alkali metal component is sodium
Solution, sodium hydroxide, sodium alkoxide
And sodium components such as sodium methoxide
You.

The ratio of the alkali metal component is not particularly limited, and is, for example, about 0.7 to 2 equivalents (based on acetoacetic ester), preferably about 0.7 to 1.1 equivalents, and more preferably about 0.7 to 1.1 equivalents. It may be about 1 equivalent. Also,
The proportion of the alkali metal component is less than 1 equivalent, for example, 0.
It may be about 7 to 0.99 equivalent (based on acetoacetate ester), preferably about 0.8 to 0.95 equivalent, more preferably about 0.9 to 0.95 equivalent. In the present invention, α-acetyl-γ-butyrolactone can be effectively obtained even if the alkali metal component is relatively small.

The alcohol as a reaction solvent includes C, such as methanol, ethanol, propanol and butanol.
_1-4 alcohol can be used. Preferred alcohols are
Methanol, ethanol, especially methanol. The reaction solvent and the alcohol component of the alkyl acetoacetate often use the same type of alcohol.

The reaction between acetoacetic ester and ethylene oxide is carried out at about room temperature, for example, about 0 to 50 ° C., preferably about 10 to 35 ° C., more preferably about 15 to 35 ° C. (particularly about 22 to 28 ° C.). Can be done with

[Alcohol Distillation Step] In the present invention, alcohol is distilled from the reaction mixture. In addition, in the production of α-acetyl-γ-butyrolactone, generally, the alcohol may be distilled off before or after the neutralization treatment described below. Is distilled off. By distilling off the alcohol before the reaction, a neutralization treatment can be performed under mild conditions, as described later, and α-acetyl-γ-butyrolactone can be efficiently obtained.

The distillation of the alcohol is preferably performed at a low temperature, and the distillation temperature is, for example, about 10 to 40 ° C., preferably about 10 to 35 ° C., and more preferably 10 to 28 ° C.
(Particularly about 20 to 28 ° C.). By evaporating the alcohol at a low temperature, the decomposition of α-acetyl-γ-butyrolactone and acetoacetic ester can be reduced.

When alcohol is distilled off at a low temperature, the alcohol is often distilled off under reduced pressure. The degree of decompression is, for example, 50 to
300 mmHg, preferably 100 to 280 mmHg,
More preferably, it is about 150 to 250 mmHg.

The alcohol distilled off may be reused as a reaction solvent after dehydration as required.

The concentration of the residual alcohol in the reaction mixture after the alcohol is distilled off is, for example, about 0.1 to 20% by weight, preferably about 0.5 to 10% by weight, and more preferably about 0.5 to 5% by weight. It is. If the alcohol concentration exceeds 20% by weight, a large amount of alcohol is dissolved in the aqueous layer during the neutralization treatment described below, and the concentrations of α-acetyl-γ-butyrolactone and acetoacetate in the aqueous layer also increase. Efficiency decreases. When the concentration of α-acetyl-γ-butyrolactone or acetoacetate in the aqueous layer increases, the rate of hydrolysis of α-acetyl-γ-butyrolactone or acetoacetate increases. further,
Since a large amount of alcohol is dissolved in the aqueous layer, sulfate (such as sodium sulfate) is easily precipitated, and the neutralization cannot be performed at a low temperature. When neutralized at high temperature, α
-Acetyl-γ-butyrolactone and acetoacetate are easily hydrolyzed. That is, when the alcohol concentration exceeds 20% by weight, α- obtained by synergistic effects such as a decrease in extraction efficiency, an increase in the hydrolysis rate due to an increase in the aqueous layer concentration, and an increase in the hydrolysis rate due to an increase in the neutralization temperature.
The amount of acetyl-γ-butyrolactone drops unexpectedly. On the other hand, if alcohol is distilled off to an alcohol concentration of less than 0.1% by weight, the production efficiency decreases.

[Neutralization treatment] The reaction mixture after alcohol distillation is neutralized with an aqueous sulfuric acid solution. The concentration of the aqueous sulfuric acid solution is, for example, about 5 to 30% by weight, preferably about 10 to 20% by weight, and more preferably about 13 to 18% by weight. When a dilute sulfuric acid aqueous solution (concentration less than 5% by weight) is used,
Production efficiency decreases. If an aqueous sulfuric acid solution exceeding 30% by weight is used, α-acetyl-γ-butyrolactone is decomposed, or the yield is reduced.

In the present invention, since the amount of alcohol in the reaction mixture is reduced to a predetermined amount, the neutralization can be performed at a relatively low temperature. The temperature of the neutralization treatment is 10
To 30 ° C, preferably about 10 to 29 ° C (for example, about 10 to 28 ° C), and more preferably 20 to 29 ° C.
° C (for example, about 20 to 28 ° C). When the neutralization temperature is 30 ° C. or higher, α-acetyl-γ-butyrolactone and acetoacetate are easily hydrolyzed, and the extraction efficiency is reduced.

In the present invention, the step of reacting the acetoacetic ester with ethylene oxide, the step of distilling off the alcohol, and the step of neutralization are preferably carried out at a temperature of about 10 to 29 ° C. (eg, about 10 to 28 ° C.). May be performed at about 20 to 29 ° C. (for example, about 20 to 28 ° C.). When all steps are performed at 10 to 29 ° C., α-acetyl-γ
-Hydroxybutyrolactone can be produced.

The pH of the neutralization solution is, for example, about 2 to 6, preferably about 2 to 4.

The neutralized solution obtained in this manner has α
-Acetyl-γ-butyrolactone and acetoacetic ester are mainly contained in the organic layer. Therefore, α-acetyl-γ-butyrolactone can be obtained from the organic layer by separating the organic layer from the aqueous layer. Although the aqueous layer of the neutralization solution also contains a small amount of α-acetyl-γ-butyrolactone and acetoacetate ester, in the present invention, since alcohol has been distilled off in advance, the aqueous layer The loss amount is small.

The ratio of α-acetyl-γ-butyrolactone in the organic layer to the total amount of α-acetyl-γ-butyrolactone in the aqueous layer and the organic layer ((amount in organic layer / (amount in aqueous layer + organic layer) The amount in the layer is, for example, about 80 to 99% (by weight), preferably about 92 to 99% (by weight).

The ratio of acetoacetate in the organic layer to the total amount of acetoacetate in the aqueous layer and the organic layer is, for example, about 80 to 99% (by weight), preferably 92 to 99% (weight basis). Weight basis).

Α-acetyl-γ-butyrolactone and acetoacetate in the aqueous layer can be further extracted with an organic solvent, if necessary.

Examples of the organic solvent include aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), ester solvents (eg, methyl acetate, ethyl acetate, butyl acetate, etc.), and ether solvents (eg, diethyl ether). , Methyl t-butyl ether, etc.), and halogen solvents (eg, methylene chloride, chloroform, etc.). The solvents may be used alone or in combination of two or more.

The amount of the organic solvent used is, for example, about 10 to 300 parts by weight, preferably about 40 to 100 parts by weight, based on 100 parts by weight of the aqueous layer.

The extraction temperature is, for example, about 10 to 40 ° C.
It is preferably about 10 to 35 ° C, more preferably 10 to 35 ° C.
It may be about 28 ° C (particularly about 20 to 28 ° C). When the reaction step, the alcohol distillation step, and the neutralization step are performed in the same temperature range, the extraction step may be performed in the same temperature range.

Α when the extract is combined with the organic layer
-The ratio of acetyl-γ-butyl lactone [extraction efficiency (recovery rate)] is the ratio of α-acetyl-γ- in the organic layer and the aqueous layer.
For example, 91 to 99 based on the total weight of butyrolactone
% (By weight), preferably 93 to 99% (by weight)
It is. The extraction efficiency (recovery rate) of the acetoacetate is, for example, 91 to 99% (weight basis), preferably 93 to 99% (weight) with respect to the total amount of the acetoacetate in the organic layer and the aqueous layer. Standard).

The yield of α-acetyl-γ-butyrolactone obtained from the organic layer or the organic layer and the extract is, for example,
About 82 to 100 mol%, preferably 85 to 95 mol%
(Based on consumed acetoacetate). The consumed acetoacetate means the remaining acetoacetate (mol) obtained by subtracting the recovered acetoacetate (mol) from the used acetoacetate (mol).

The organic layer and the extract may be used, if necessary,
It may be purified by concentration and rectification.

The α-acetyl-γ thus obtained
-Butyrolactone can be used as an intermediate for pharmaceuticals such as vitamin B1 and organic industrial chemicals.

[0036]

According to the present invention, the alcohol is used in an amount of 0.1 to 20.
Since it is concentrated to about% by weight, α-acetyl-γ-butyrolactone can be efficiently produced under mild conditions. For example, the temperature of the neutralization treatment can be reduced to about 10 to 29 ° C. Therefore, α-acetyl-γ-
Hydroxybutyrolactone can be obtained, and the production cost of α-acetyl-γ-butyrolactone can be reduced.

[0037]

The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 31.5 g of sodium hydroxide was dissolved in 284 g of methanol, 99 g of methyl acetoacetate and 41 g of ethylene oxide were added, and the mixture was reacted at 25 ° C. for 13 hours. The methanol was distilled off from the reaction solution under reduced pressure (200 mmHg) using a thin film evaporator (75 ° C. in the thin film evaporator), and the reaction solution was recovered. The methanol concentration in the mixture after methanol distillation is
It was about 10% by weight. The mixture is stirred at 28 ° C. for 1 hour.
273 g of a 5% by weight aqueous sulfuric acid solution was added, and pH = 2.5.
And left to stand. This operation required 45 minutes. After standing, a sample was sampled from the upper layer (organic layer) and the lower layer (aqueous layer) separated by two layers, and analyzed by high performance liquid chromatography. The upper layer (organic layer) showed α-acetyl-
52.5% by weight (61.9 g) of γ-butyrolactone;
Methyl acetoacetate was dissolved at 27.4% by weight (32.3 g) and the methanol concentration was 2.2% by weight. In the lower layer (aqueous layer), α-acetyl-γ-butyrolactone contains 1.5%.
% By weight (4.8 g), 0.9% by weight of methyl acetoacetate
(1.1 g) and 4.2% by weight of methanol were dissolved. After separating the organic layer and the aqueous layer, the aqueous layer was extracted at 28 ° C. with 400 g of toluene. From the organic layer and the extract, α
-Acetyl-γ-butyrolactone was obtained in an amount of 64.0 g. The yield and extraction efficiency were as follows.

Yield: 88.0 mol% of α-acetyl-γ-butyrolactone
(Based on consumed acetoacetate ester) Extraction efficiency: α-acetyl-γ-butyrolactone 96% Methyl acetoacetate 95% Comparative Example 1 31.5 g of sodium hydroxide was dissolved in 284 g of methanol, and 99 g of methyl acetoacetate and 41 g of ethylene oxide were added. After the addition, the reaction was performed at 25 ° C. for 13 hours. The methanol was distilled off from the reaction solution under reduced pressure (300 mmHg) using a thin film evaporator (the thin film evaporator had a bottom temperature of 85 ° C.) and was recovered. The methanol concentration in the mixture after methanol distillation is
It was about 23% by weight. The mixture is stirred at 55 ° C. for 1 hour.
273 g of a 5% by weight aqueous sulfuric acid solution was added, and pH = 2.5.
And left to stand. This operation required 45 minutes. After standing, a sample was sampled from the upper layer (organic layer) and the lower layer (aqueous layer) separated by two layers, and analyzed by high performance liquid chromatography. The upper layer (organic layer) showed α-acetyl-
49.8% by weight (56.3 g) of γ-butyrolactone;
Methyl acetoacetate was dissolved at 26.1% by weight (29.5 g) and the methanol concentration was 5.0% by weight. In the lower layer (aqueous layer), α-acetyl-γ-butyrolactone contains 2.1.
% By weight (6.9 g), 1.5% by weight of methyl acetoacetate
(1.1 g), and 10.2% by weight of methanol was dissolved. After separating the organic and aqueous layers, the aqueous layer was
Extracted with 400 g of toluene. From the organic layer and the extract,
60.1 g of α-acetyl-γ-butyrolactone was obtained.
The yield and extraction efficiency were as follows.

Yield: 78.8 mol% of α-acetyl-γ-butyrolactone
(Based on consumed acetoacetate) Extraction efficiency: α-acetyl-γ-butyrolactone 94% Methyl acetoacetate 92%

Claims (6)

[Claims] A mixture obtained by reacting acetoacetic ester and ethylene oxide in an alcohol solvent in the presence of an alkali metal component is neutralized with an aqueous sulfuric acid solution, and α-acetyl-γ-butyrolactone is separated from the separated organic layer. , The alcohol is distilled off before the neutralization treatment, the residual alcohol concentration in the reaction mixture is adjusted to 0.1 to 20% by weight, and the mixture is neutralized with a sulfuric acid aqueous solution at a temperature of 10 ° C or more and less than 30 ° C. A method for producing α-acetyl-γ-butyrolactone. 2. The method according to claim 1, wherein the step of reacting the acetoacetic ester with ethylene oxide, the step of distilling off the alcohol, and the step of neutralization are carried out at a temperature of 10 to 28 ° C. 3. An acetoacetic acid ester having a concentration of 0.7 to
2. The method according to claim 1, wherein 1.1 equivalents of an alkali metal component is used. 4. An acetoacetic acid ester, wherein the acetoacetic acid ester is
The production method according to claim 1, which is a _1-4 alkyl ester. 5. The method according to claim 1, wherein α-acetyl-γ-butyrolactone is further extracted from the aqueous layer after the layer separation. 6. A method for producing methyl acetoacetate and ethylene oxide,
The reaction is carried out in methanol in the presence of 0.8 to 0.95 equivalent (based on methyl acetoacetate) of sodium hydroxide, and methanol is distilled off until the residual methanol concentration in the reaction mixture becomes 0.5 to 5% by weight. And neutralized with a 13 to 18% by weight aqueous sulfuric acid solution.
The method according to claim 1, wherein γ-butyrolactone is obtained, wherein the reaction step, the methanol distillation step, and the neutralization step are performed at 20 to 28 ° C.