JPS6165838A - Production of alpha-(p-isobutylphenyl)propionic acid - Google Patents

Abstract

PURPOSE:To obtain the titled compd. useful as antipyretic, analgesic and antiphlogistic with excellent high selectivity, by oxidizing alpha-(p-isobutylphenyl) propionaldehyde acid with a hypohalite in the presence of acetic acid at a specified reaction temp. CONSTITUTION:alpha-(p-Isobutylphenyl)propionaldehyde (IPN) is oxidized with one or more hypohalites selected from NaClO, KClO, Ca(ClO)2, NaBrO, KBrO etc., in the presence of acetic acid, at <=-12 deg.C, preferably -12--50 deg.C, to obtain the titled compd. useful as pharmaceuticals having less side effects with a surprisingly high efficiency, e.g. >=97% selectivity and >=95% yield. The amount of the hypohalite to be used is <=1mol, preferably <=1.05mol based on 1mol IPN. The amount of the acetic acid to be present is enough to make the reaction system neutral - acidic, usually >=0.1mol, preferably >=0.2mol based on 1mol hypohalite.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing α-(p-isobutylphenyl)propionic acid. More specifically, α-(p-isobutylphenyl)propionaldehyde is oxidized with hypohalite under specific reaction conditions,
The present invention relates to a method for producing α-(p-isobutylphenyl)propionic acid.

α-(P-isobutylphenyl)propionic acid (IPA) obtained by the method of the present invention is a useful compound as a substance with few side effects having antipyretic, analgesic, and antiinflammatory effects.

[Prior Art and Problems to be Solved] Conventionally, many methods have been proposed for producing IPA by oxidizing α-(p-isobutylphenyl)propionaldehyde (IPN). JP-A-49-9593 using a silver compound
No. 8, JP-A-58-35140 and French Patent No. 1,545,270, JP-A-51 using permanganate
-100042, JP-A-51-1.01! J49 and JP 52-97930 and JP 51-10042, JP 53-7643 and JP 54 using oxidizing agents such as chromic acid, harsh, hydrogen peroxide and chlorite. -39043 etc. are mentioned as an example. However, in these methods, the target object I
This method has drawbacks such as low selectivity to PA and the use of expensive substances as an oxidizing agent, and is not satisfactory as a method for industrial implementation.

Furthermore, Japanese Patent Application Laid-open No. 18534/1983 discloses a method for producing IPA by oxidizing IPN with hypohalogenated alcohol in the presence of acetic acid. This method uses inexpensive reagents and is easy to handle. Furthermore, this is a preferred method because side reactions can be easily controlled.

However, it cannot be said that this method is necessarily satisfactory in terms of selectivity and the like.

The inventors discovered that when oxidizing IPN with hypohalous acid, IPN can be oxidized with excellent selectivity if oxidized under specific conditions.
The present invention was completed by discovering that PA can be obtained.

[Means for solving the problems] That is, the present invention provides α-(p-isobutylphenyl)
Propionaldehyde in the presence of acetic acid at a temperature of -12
The present invention provides a method for producing α-(p-isobutylphenyl)propionic acid, which is characterized in that it is oxidized using a hypohalite at a temperature of 0.degree. C. or lower.

The present invention will be further explained below.

Hypochlorite/\rogenate salts used in the production method of the present invention include primary sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, and potassium hypobromite. The amount of the zero hypohalite salt, which can be used as a salt itself or as an aqueous solution, is equal to or more, preferably 1.05 mole or more, per 1 mole of IPN. There is no particular upper limit, but
In practical terms, the amount is up to 50 mol per mol of IPNI.

The amount of acetic acid present is sufficient to make the reaction system neutral or acidic, and the amount is usually 0.1 mol or more, preferably 0.2 mol or more per 1 mol of the hypohalite. It is. Regarding the upper limit, it is not necessary to add a particularly large amount of acetic acid, and in practical terms it is 50 times the molar amount or less.

In the present invention, it is important to carry out the reaction temperature at -12°C or lower, preferably -15°C or lower.

That is, the oxidation reaction itself by the hypohalite proceeds rapidly, and the reaction rate shows a high value of 99 to 100%. However, p-isobutylacetophenone (BAP) is usually produced as a by-product due to a side reaction. The temperature dependence of this side reaction is remarkable, and the IPA/BAP molar ratio, which indicates the selectivity of the target product IPA, changes critically around the reaction temperature of -12°C, and when the temperature is higher than -12°C. , the IPA/BAP production molar ratio rapidly decreases.

Therefore, the lower limit of the 0 reaction temperature, which is undesirable because a reaction temperature higher than -12°C will drastically reduce the selectivity of IPA, is not particularly limited. Depends on the conditions, usually -50'C! That's it.

Furthermore, during oxidation, it is possible to use an inert solvent that does not coagulate or freeze at low temperatures and has sufficient solubility in IPA and the like. Examples of these solvents include water-soluble solvents such as ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran, dioxane, and diglyme, alcohols such as methanol, ethanol, and ethylene glycol, as well as paraffins such as hexane, Examples include non-aqueous solvents such as naphthenes such as cyclohexane, aromatic hydrocarbons such as benzene and toluene, but water-soluble solvents give more preferable results.

[Function and Effect] As described above, according to the method of the present invention, by oxidizing α-(p-isobutylphenyl)propionaldehyde (IPN) under specific reaction conditions, a selectivity of 97% can be achieved.
With the above, α-(
p-inbutylphenyl) propion M (IPA) 5! can be built.

The present invention will be explained in detail with reference to Examples below.

[Example] In a flask with a stirrer with a capacity of 2001, IPNl 0
g (53 mmol), 7.2 g of acetic acid, and acetone 301 as a solvent were added, and the mixture was cooled to the temperatures shown in FIG. At each temperature, 42.8 g of 10% sodium hypochlorite aqueous solution (58 ma+ol as hypochlorous acid)
was gradually added dropwise. After the completion of the dropwise addition, the reaction was further stirred for 1 hour. After the completion of the reaction, the oil layer was analyzed by liquid chromatography to determine the reaction rate of IFN and IPA/BA.
The molar ratio of P was determined.

The reaction rate is 99-100% at any reaction temperature.
showed a high value.

In addition, IPA/BAP is used as an indicator of product selectivity.
Figure 1 shows the molar ratio of . As can be seen from the figure, I
The molar ratio of PA/BAP changes critically around -12°C, and at a reaction temperature of -12°C or lower, the target product IP
It was observed that the selectivity of A was significantly improved.

[Brief explanation of drawings]

Figure 1 shows the reaction temperature and molar ratio of reaction products (IP, A/
It is a graph showing the relationship with BAP).

Claims (3)

[Claims] (1) α-(p-isobutylphenyl)propionaldehyde is oxidized using hypohalite in the presence of acetic acid at a temperature of -12°C or below. ) Method for producing propionic acid. (2) The method for producing α-(p-isobutylphenyl)propionic acid according to claim 1, wherein the temperature is in the range of -12°C to -50°C. (3) The hypohalite is at least one compound selected from the group of sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, and potassium hypobromite. The first claim is
A method for producing α-(p-isobutylphenyl)propionic acid as described in 1.