JPH04149154A - Production of 2,4-dioxo-4-phenylbutyric acid ester - Google Patents

Abstract

PURPOSE:To economically obtain the title compound in high yield without solidifying a reaction mixture by subjecting acetophenone and a dialkyl oxalate to condensing reaction in the presence of a sodium alkoxide using an organic solvent separable from water. CONSTITUTION:Acetophenone and a dialkyl oxalate are subjected to condensing reaction in the presence of a sodium alkoxide using an organic solvent (toluene, etc., are especially preferred) separable from water as a reaction solvent to afford a 2,4-dioxo-4-phenylbutyric acid ester. Since the fluidity of the reaction mixture is always kept according to the aforementioned method without causing trouble such as solidification, control in mass production is facilitated. Furthermore, since a high reaction concentration can be set, production efficiency is improved and the above-mentioned method is economically advantageous. Nearly quantitative high yield can further advantageously be attained.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention provides 2-oxo-4- which is an intermediate for antihypertensive agents.
The present invention relates to a method for producing 2,4-dioxo-4-phenylbutyric acid ester, which is a precursor of phenylbutyric acid and 2-hydroxy4-phenylbutyric acid.

<Prior art> Conventionally, as a method for producing ethyl 2,4-dioxo-4-phenylbutyrate, there has been a method in which diethyl oxalate and acetophenone are reacted with metallic sodium at 0 to 5°C in anhydrous ethanol (Bull, soc, chim
, France.

1958.687-694) are known.

Generally, methods for synthesizing ethyl acylpyruvate by condensing methyl ketone with diethyl oxalate in the presence of sodium ethoxide include, for example, Org;
Syn, Co11°Vol, 1. p, 238
Org, Syn.

Co11. The method described in Vol. U. p. 1.26 is known.

<Problems to be Solved by the Invention> However, when the present inventors tried the former method, the yield was not necessarily as bad as described in the literature (80.4%), but the product was not produced in the middle of the reaction. was precipitated in the form of a slurry, and the reaction system became semi-solid, making stirring impossible.

This solidification occurred with good reproducibility even at a feed concentration of 10% by weight, which is by no means a high concentration. In the laboratory, such solidification can be adequately dealt with, but in large-scale industrial production, solidification of the contents of the reactor renders subsequent operations impossible. However, lowering the feed concentration for the reaction lowers the production efficiency and causes many industrial problems.

Means for Solving the Problems> Therefore, the present inventors conducted various studies to solve the above problems, and found that when an appropriate organic solvent such as a hydrocarbon is used, They discovered that the problematic solidification of the reaction system did not occur, and completed the present invention.

That is, the above object of the present invention is to produce 2,4-dioxo-
Achieved by adopting a method for producing 2゜4-dioxo-4-phenylbutyric acid ester, which is characterized in that, when producing 4-phenylbutyric acid ester, the reaction is carried out in the presence of an organic solvent that can be separated from water. be done.

The details of the configuration of the present invention will be explained below.

In the present invention, the dialkyl oxalate used as a raw material is, for example, diethyl oxalate and dimethyl oxalate. Although either ester reacts similarly, it is preferable to use an oxalate ester having the same alkoxy group as the alkoxy group of the target 2,4-dioxo-4-phenylbutyric acid ester. The reason for this is that when an oxalate ester having an alkoxy group different from that of the target product is used, it is necessary to convert it into the target alkoxy group in a subsequent step, which is economically disadvantageous.

In the present invention, sodium alkoxide is, for example, sodium ethoxide and sodium methoxide. Either reacts in the same way, or, like dialkyl oxalate, reacts with the desired 2,4-dioxo-4-
It is preferable to use sodium alkoxide having the same alkoxy group as that of phenylbutyric acid ester. In other words, it is more preferable to use a sodium alkoxide having the same alkoxy group as the alkoxy group of the oxalic acid dialkyl ester used. The reason for this is that in the presence of a metal alkoxide, or generally in the coexistence of an alkali and an alcohol, the alkoxy group of the ester undergoes a so-called transesterification reaction, resulting in a mixture.

As the sodium alkoxide used in the present invention, powders or solutions of sodium ethoxide or sodium methoxide which are commercially available as reagents may be used as they are, or they may be prepared from metallic sodium and ethanol or methanol before use.

As is well known, sodium ethoxide and sodium methoxide are unstable with respect to moisture and oxygen, so it is preferable to store them while avoiding contact with these and to use those with sufficient activity.

In the present invention, the reactants acetophenone, oxalic acid dialkyl ester, and sodium alkoxide are generally used in equivalent amounts.

In this case, all of the reactants will be consumed, resulting in no waste and is economically advantageous.

However, it is preferable to use the sodium alkoxide in excess of, for example, 1 to 20 mol % relative to the dialkyl oxalate ester, since the adverse effects of moisture mixed into the reaction system can be offset. In addition, for example, oxalic acid dialkyl ester can be added to acetophenone in a range of 0.5 to
Even if it is used at a molar ratio of 3 times, there is no problem in the reaction. In such instances, the oxalic acid dialkyl ester used in excess would rather act as a solvent.

In the present invention, it is important to carry out the condensation reaction in the presence of an organic solvent that can be separated from water. In the present invention, the organic solvent that can be separated from water includes organic solvents that do not form a homogeneous phase with water, but also includes organic solvents that do not form a homogeneous phase with an aqueous salt solution.

Generally, sodium alkoxide is often used in the alcohol used to produce the alkoxide, but in the present invention, an organic solvent that can be separated from water is used as the solvent in order to prevent the reaction system from solidifying. Solvents that can be used are those that are inert under the reaction conditions. Preferable examples of such a solvent include aromatic hydrocarbons, ethers, and mixed solvents thereof, and most preferably, toluene is used. Further, these solvents may contain alcohol within a composition range that can be separated from water during the liberation treatment described below. However, in this case, the alcohol preferably has the same alkoxy group as the alkoxy group of the dialkyl oxalate ester used for the reason of the transesterification reaction described above.

The amount of the water-separable organic solvent used in the present invention is the amount necessary to maintain appropriate fluidity of the reactant, and is usually 4 to 200 times the weight of acetophenone.

The method of the present invention is preferably carried out at a temperature of -20°C or higher and +50°C or lower. More preferably, the temperature is 5°C or higher and 40°C or lower. When the reaction temperature is lower than 120° C., it takes too much time to complete the reaction, resulting in poor production efficiency and is economically disadvantageous. On the other hand, the reaction temperature is +50℃
As the temperature increases beyond this point, the yield gradually decreases due to the occurrence of side reactions.

One thing to note is the order in which the reactants sodium alkoxide, oxalic acid dialkyl ester, and acetophenone are added. That is, as is known, acetophenone self-condenses in the presence of sodium alkoxide, and this must be avoided as much as possible.

The order of addition for this purpose is, for example, first adding the solvent to the sodium alkoxide, then adding the oxalic acid dialkyl ester, and then adding the acetophenone. It is also possible to add a premixed dialkyl oxalate ester and acetophenone to a solvent to which sodium alkoxide has been added.

In the present invention, as shown in the following formula, (1) (II) surface ■ Acetophenone (1) and oxalic acid dialkyl ester (
By condensation with II), a sodium interface of 2,4-dioxo-4-phenylbutyric acid ester is first formed. In order to liberate this and obtain the desired 2,4-dioxo-4-phenylbutyric acid ester, it may be treated with an appropriately diluted mineral acid according to a known method. Examples of mineral acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

By treatment with diluted mineral acids, the organic solvent layer containing the target product separates from the aqueous layer.

This aqueous layer can be extracted with a suitable organic solvent if necessary. The organic solvent in this case may be the same as or different from that used previously in the condensation reaction. By concentrating the organic layer obtained in this way, the desired 2,4-dioxo-
4-phenylbutyric acid ester is obtained.

<Example> Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Under a dry nitrogen atmosphere, 18.7 g of sodium ethoxide suspended in 145 ml of toluene was added at 20°C or above.
Diethyl oxalate 38.3 while keeping the temperature below 5℃
g was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. At the same temperature, 30°Og of acetophenone was added dropwise over 30 minutes, and the mixture was further stirred for 1 hour. Add 20ml of concentrated sulfuric acid to the reaction mixture.
A mixture of 1 and 80 ml of water was added, and the organic layer was separated.

Quantitative analysis using high performance liquid chromatography confirmed the production of 54.8 g (yield: 99.8%) of ethyl 2,4-dioxo-4phenylbutyrate in this organic layer.

Example 2 Under a dry nitrogen atmosphere, 64.3 g of diethyl oxalate was added dropwise over 1 hour to 30.0 g of sodium ethoxide suspended in 400 ml of toluene while maintaining a temperature of 5° C. or higher and 10° C. or lower. Stir for hours. At the same temperature, 4,860 g of acetophenone was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. A mixture of 50 ml of concentrated sulfuric acid and 200 ml of water was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted twice with 100 ml of toluene. This organic layer was concentrated under reduced pressure and further distilled under reduced pressure to obtain 80.0 g (yield 90.9%) of ethyl 135-b-thioxo-4-phenylbutyrate.-Melting point 40-42°C.

Example 3 After adding 5.0 g of finely chopped metallic sodium to 100 ml of toluene under a dry nitrogen atmosphere, 40 ml of ethanol was added dropwise while heating the mixture to 75°C. After the metallic sodium was completely dissolved, a mixture of 24.0 g of acetophenone and 32.1 g of diethyl oxalate was added dropwise over 1.5 hours while maintaining the temperature between -5°C and +5°C. After stirring for an additional hour at room temperature, the same post-treatment as in Example 2 was carried out to obtain 41.0 g (yield: 93.2%) of ethyl 2.4-dioxo-4-phenylbutyrate.

Example 4 Under a dry nitrogen atmosphere, into 15.0 g of sodium ethoxide suspended in 200 ml of toluene at a temperature of 5° C. or higher and 10° C.
A mixture of 30.7 g of diethyl oxalate and 24.0 g of acetophenone was added dropwise over 1.5 hours at the following temperature. After the dropwise addition, after further stirring at room temperature for 4 hours, Example 2
The same post-treatment as above was performed to obtain 40.9 g (yield 93.0%) of ethyl 2,4-dioxo-4-phenylbutyrate.

Example 5 Under a dry nitrogen atmosphere, inject into 30.0 g of sodium ethoxide suspended in 400 ml of toluene at 30°C or higher and 35°C.
62.0 g of diethyl oxalate while maintaining the temperature below.
was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. At the same temperature, 48.0 g of acetophenone was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. The same post-treatment as in Example 2 was carried out to give ethyl 2°4-dioxo-4-phenylbutyrate81.
3 g (yield 92.4%) was obtained.

Example 6 Under a dry nitrogen atmosphere, into 17.0 g of sodium ethoxide suspended in 300 ml of toluene at 20°C or higher and 30°C
73.0 g of diethyl oxalate while maintaining the following temperature:
was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. At the same temperature, 30.0 g of acetophenone was added dropwise over 30 minutes.
The mixture was further stirred for 1 hour. The same post-treatment as in Example 2 was carried out, and the obtained organic layer was quantitatively analyzed by high-performance liquid chromatography. As a result, 54.2 g of ethyl 2,4-dioxo-4-phenylbutyrate (yield 98.5%) was obtained. Confirmed generation.

Example 7 Under a dry nitrogen atmosphere, 15.0 g of sodium ethoxide was added to 18.7 g of sodium ethoxide suspended in 150 ml of tetrahydrofuran.
38.3 g of diethyl oxalate was added dropwise over 30 minutes while maintaining the temperature between 20° C. and above, followed by further stirring for 30 minutes. At the same temperature, 30 g of acetophenone was added dropwise over 30 minutes, and the mixture was further stirred for 1 hour. A mixture of 20 ml of concentrated sulfuric acid and 80 ml of water was added to the reaction mixture, and the mixture was extracted with 1.50 ml of toluene. Quantitative analysis using high performance liquid chromatography revealed that 2.4-
Ethyl dioxo-4-phenylbutyrate 54°4g (yield 9
8.9) was confirmed to be produced.

Comparative Example 1 The same reaction as in Example 2 was carried out at 60°C and the same post-treatment was carried out, and the yield of ethyl 2.4-dioxo-4-phenylbutyrate was 63.5%.

Comparative Example 2 Under a dry nitrogen atmosphere, 5.0 g of metallic sodium was added little by little to 100 ml of ethanol and dissolved. While keeping this solution at a temperature above -5°C and below +5°C, acetophenone 24
．． , Og and 312 g of diethyl oxalate were added dropwise over 1 hour. After stirring at room temperature for 2 hours, the viscosity of the slurry gradually increased and the entire system seemed to solidify, so 100 m of ethanol was added. Still 3
After 0 minutes, it seemed to solidify again, so I added ethanol 10
An additional 0 ml was added. However, 30 minutes later, the entire system was completely solidified, so after adding 100 ml of ethanol and 100 ml of toluene, the solidified matter was loosened with a metal spatula. 10ml concentrated sulfuric acid and 400ml water
After adding a mixture of 2,4-
36.1 g of ethyl dioxo-4-phenylbutyrate (yield: 82
,0%) was obtained.

<Effect of the invention> The present invention has the following effects.

a1 In the present invention, the fluidity of the reaction mixture is always maintained and there are no problems such as solidification, so it is easy to control during mass production.

b. Furthermore, since the reaction concentration can be set as high as about 40% by weight, production efficiency is improved and it is economically advantageous.

C8 According to the method of the present invention, an almost quantitatively high yield can be obtained.

Claims (2)

[Claims] (1) When producing 2,4-dioxo-4-phenylbutyric acid ester by condensing acetophenone with dialkyl oxalate in the presence of sodium alkoxide, the presence of an organic solvent that can separate the reaction from water. 2,4-dioxo-4-, characterized in that
Method for producing phenylbutyric acid ester. (2) The method for producing 2,4-dioxo-4-phenylbutyric acid ester according to claim 1, wherein the reaction is carried out at a temperature of -20°C or higher and +50°C or lower.