JPS60190736A - Preparation of aromatic alpha-keto acid - Google Patents

Abstract

PURPOSE:To obtain an aromatic alpha-keto acid useful as a synthetic raw material for aromatic alpha-amino acids, alpha-hydroxy acids, etc., easily in high yield without decarbonylation, by hydrolyzing an aromatic alpha-keto acid amide with an aqueous solution of an alkali. CONSTITUTION:One equivalent aromatic alpha-keto acid amide of the formula (R<1> is aromatic group such as aryl, pyridyl or thienyl; R<2> and R<3> are H or alkyl, and one thereof is alkyl or R<2> and R<3> together may form a ring), e.g. benzoyl-N,N- diethylformamide, easily obtained by reacting an aromatic halide with a primary or secondary amine and CO in the presence of a Pd catalyst is dissolved or suspended in preferably 10-50 equivalents aqueous solution of an alkali (earth) metal hydroxide, e.g. 0.5-3N NaOH, heated under vigorous agitation and hydrolyzed for 1-12hr to give the aimed compound, e.g. benzoylformic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for hydrolyzing aromatic α-keto El amide to produce aromatic α-1[-] in a still yield.

It is generally well known that α-keto acids are highly reactive compounds having two adjacent carbonyl groups, and are easily converted into α-amino acids, α-oxy acids, and the like. However, until now, it has not been easy to synthesize aromatic α-keto acids, so the route to synthesize industrially useful aromatic α-amino acids and α-oxy acids using them as raw materials has been blocked.

In addition, the aromatic α-keto acid amide used as a raw material in the present invention was prepared by combining an aromatic herodanide and a first compound according to a method previously developed by two of the present inventors, Akio Yamamoto and Fumiyuki Ozawa. It can be easily obtained by reacting a primary amine or a secondary amine and carbon oxide in the presence of a palladium catalyst (see JP-A-58-152846).

Until now, there have been no reports on the hydrolysis of α-keto acid amide (M*Barre reported the use of 6N hydrochloric acid to hydrolyze α-oxobutyric acid diethylamide as an aliphatic α-keto acid amide). It is only being done,
Hydrolysis with alkali is considered to be unsuitable because the α-keto acid produced is unstable to alkali (C
ompt, R@nd, v 184825 (1927
)).

The present inventors investigated aromatic α-
We investigated the hydrolysis of keto acid amides, but confirmed that the reaction hardly progressed even under the severe conditions of 12N hydrochloric acid reflux. Conventionally, the hydrolysis of carboxylic acid amides was carried out using a) mineral acids such as hydrochloric acid or A method of adding acetic acid to acid, dissolving it, and heating it.

b) A method of dissolving in an alcoholic solution of caustic soda, an alkali metal hydroxide such as caustic potash, or an alcoholic aqueous solution thereof and heating the solution. A more special example is C) a method of reacting with sodium peroxide. d)
Method of heating with 100% phosphoric acid. e) A method is known in which a carboxylic acid amide is nitrosylated with a nitrite, an alkyl nitrite, nitrosyl chloride, nitrogen dioxide, etc., and this is decomposed into a carboxylic acid. When the ice-breaking reaction of these carboxylic acid amides is applied to the hydrolysis of aromatic α-keto acid amides, the reaction hardly progresses in a) as mentioned above, and in e) the reagents are expensive. Therefore, it is unsuitable for industrial use! 0, d), no satisfactory results were obtained. In addition, e) is impossible because carmenic acid amide, which is a secondary amine, is not nitrosated, and extremely toxic nitrous acid gas is generated, so it cannot be said to be a useful method. Furthermore, when method b) was applied to aromatic α-keto acid amide, and the aromatic α-keto acid amide was dissolved in an aqueous medium containing methanol, dioxane, etc. and heated, hydrolysis proceeded easily, but the aromatic α-keto acid amide A side reaction of decargenylation occurred, producing a large amount of aromatic carboxylic acid.

Therefore, the present inventors decalcified aromatic α-keto acid amides.
As a result of extensive research into a hydrolysis method that does not cause IP-nylation, we unexpectedly found that an aromatic α-keto acid anolyte was dissolved or suspended only in an alkaline aqueous solution, and the solution was heated and stirred at an appropriate temperature for the required time. We discovered that aromatic α-keto acids can be obtained in high yield without decalcification and nylation.
The present invention has now been completed.

As described above, the discovery that hydrolysis of aromatic α-keto acid amide can proceed extremely smoothly without causing side reactions such as decarboxylation by acting only on aqueous alkaline solutions was completely unexpected. This is noteworthy. Note that the rate of hydrolysis reaction tends to be slightly slower than in hydrous alcohol, but this is not a problem for practical use. The aromatic α-keto acid amide used in the present invention is
R2 and BS represent hydrogen or an alkyl group, at least one of which is an alkyl substituent. Also, a2 and B S may be linked to each other to form a ring).

Representative examples of aromatic α-keto acid amides include benzoylformic acid diethylamide, benzoylformic acid-1-butylamide, 9-hydroxypenzoylformic acid diethylamide,
Examples of the alkaline aqueous solution used in the present invention include 2-pyridyl-glyoxylic acid diethylamide, but are not limited to those that are soluble in aqueous alkaline solutions. Examples of the aqueous alkaline solution used in the present invention include caustic soda, alkali metal hydroxides such as caustic potash, and calcium hydroxide. Examples include aqueous solutions of alkaline earth metal hydroxides.

To carry out the present invention, an aqueous alkaline solution of about 0.5 to 3N is preferably dissolved or dissolved in an appropriate amount of 10 to 50 equivalents, and if necessary, a larger amount if necessary, per 1 weight of aromatic α-keto acid amine P. When suspended and heated with vigorous stirring, approximately 1
Hydrolysis is complete in ~12 hours. The rate of hydrolysis requires a long time at room temperature, but increases with increasing temperature when heated. Furthermore, the concentration of the alkaline aqueous solution has little to do with it, but rather depends on the number of moles used, and it is not preferable to use a highly concentrated alkaline aqueous solution since decalcification tends to cause nylation. For example, when 20 equivalents of a 2N caustic soda aqueous solution are suspended in benzoylformic acid diethylamide, stirred vigorously, and heated to reflux, the reaction solution becomes homogeneous and the hydrolysis is completed in 10 hours.

Completion of the reaction can be confirmed by thin layer chromatography and gas chromatography after extracting a portion of the reaction solution, making it acidic with dihydrochloric acid, extracting with ethyl acetate, and silylating. To isolate the product, the aqueous solution that has been hydrolyzed as described above is subjected to an appropriate extraction operation and then crystallized to obtain the desired aromatic α-keto acid in high yield.

This will be specifically explained below using examples.

Example 1 Benzoylformic acid diethylamide 4111n9 was suspended in 2N caustic soda 20117, and while stirring vigorously, 1
After heating under reflux for 0 hours, the reaction solution becomes homogeneous. After cooling, the solution was adjusted to pH 2 by adding 6N hydrochloric acid, extracted with ethyl acetate, concentrated under reduced pressure, and the resulting crystals were recrystallized from carbon tetrachloride, removed and dried to obtain 270 mg of benzoylformic acid. Yield: 90.0 cm.

Example 2 /4-Hydroxypenzoylic acid diethylamide 1.
11 gr was dissolved in 251 d of 2N caustic soda and heated under reflux for 12 hours with stirring. After cooling, add 6N to this solution.
Add hydrochloric acid to adjust to pl (4), concentrate under reduced pressure, dry under reduced pressure, filter the precipitated salt with ethyl acetate, concentrate the filtrate under reduced pressure, and recrystallize the obtained crystals from ether/petroleum ether.
When taken in a furnace and dried, p-hydroxybenzoylformic acid 711
mgr is obtained.

Yield: 85.6% Example 3 3-pyridyl-glyoxalic acid diethylamide 727
mgr is dissolved in 2N caustic soda 251d and heated under reflux for 2 hours. After cooling, 6N hydrochloric acid was added to the kernel solution to adjust the concentration to -4, and the solution was concentrated under reduced pressure).
Sodium chloride was filtered out from the mixture of sodium chloride using ethanol, and the filtrate was concentrated under reduced pressure to give a solution of about 4-4-chloride.
．． Add 5 d, phenylhydrazine Q, 35 d and 30
It was allowed to react for a minute. The reaction solution was concentrated under reduced pressure, and the resulting crystals were crystallized in ethanol/chloroform to give 702 mg of phenylhydrazotu 3-pyridyl-glyoxalate hydrochloride.
r is obtained. Yield 84.3%.

Example 4 411 mgr of benzoylformic acid-1-butylamide to 2
Suspended in 20-N caustic soda and stirring vigorously,
When heated under reflux for a period of time, the reaction solution becomes homogeneous. After cooling, 6N hydrochloric acid is added to this solution to adjust the pH to 2, extracted with ethyl acetate, concentrated under reduced pressure, and the resulting crystals are recrystallized from carbon tetrachloride. The residue was taken, dried, and hydrolyzed with an acid amide under alkaline conditions to give the corresponding α-keto acid.

The obtained results are shown in Table 1 along with the raw materials used and reaction conditions.

Claims (1)

[Claims] A method for producing an aromatic α-keto acid, which comprises hydrolyzing an aromatic α-keto acid amide by heating it with an alkaline water bath.