JPS5924969B2 - Production method of α-diketones - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing α-diketones.

More specifically, the present invention relates to a method for producing benzoyl alkyl ketones. The α-diketones targeted in the present invention are extremely useful compounds as intermediates for pharmaceuticals.

For example, 4-isobutylbenzoylmethylketone can be rearranged to produce α-hydroxy α-(4-
isobutylphenyl)-propionic acid 9. α-Hydroxy-α-(4-isobutylphenyl)-propionic acid, for example British Patent No. 971,
α-1(4-isobutylphenyl)-propionic acid can be easily derived by the method described in No. 700, and is known to have excellent anti-inflammatory analgesic effects. Therefore, α-
Diketones are extremely valuable compounds, for example as intermediates for pharmaceuticals as mentioned above. Conventionally, various methods for producing α-diketones have been proposed, but each method has its own drawbacks when it comes to industrial implementation.

For example, the method of using ketones as a raw material and reacting selenium oxide with it requires a step of treating the product and waste liquid because the selenium compound is toxic. This poses a problem when it comes to implementation.

On the other hand, the method in which ketones are reacted with nitrosyl chloride to isonitrosate and then hydrolyzed has the disadvantage that the equipment is expensive due to the toxicity and corrosivity of the reagents used, and there are many reaction steps.

Therefore, the present inventors conducted research on a method for obtaining diketones without the drawbacks of the conventional methods as described above, and as a result, they arrived at the present invention. That is, the present invention is a general type seal O Ar-C-CH2-R...
[l] (In the formula, Ar represents a substituted or unsubstituted aromatic hydrocarbon ring, and R represents an aliphatic group.

) is reacted with molecular oxygen or molecular oxygen-containing gas in the presence of a basic reagent. - A method for producing diketones.

According to the method of the present invention, the ketone represented by the above formula [] can be directly converted to α-diketones represented by the formula [2], and the problems of toxicity and corrosivity of the reagents used can be virtually eliminated. few. Ar in the formula u used in the method of the present invention may be any substituted or unsubstituted aromatic hydrocarbon ring, and the group may be substituted with an inert substituent. . Such substituents include alkyl groups having 1 to 12 carbon atoms, alkoxy groups having 1 to 12 carbon atoms, aryloxy groups having 15 or less carbon atoms,
Preferred examples include halogen atoms and the like.

One to three of these substituents may be substituted. On the other hand, R in the above formula u] is an aliphatic group, particularly having 1 to 10 carbon atoms.
is advantageous.

The aliphatic group may be straight, branched or cyclic, and the saturated region may be unsaturated. Among these, aliphatic groups having 1 to 4 carbon atoms are preferred, and methyl and ethyl groups are most preferred. Such R may have a substituent, and examples of the substituent include carbon atoms of 1 to 1.
An alkoxy group of 2, an allyloxy group having 15 or less carbon atoms, a halogen atom, etc. are preferable. Preferred specific examples of the ketone represented by the above formula U] include 4-isobutylphenylethyl ketone, 4-Tertbutylphenylethyl ketone, 4-cyclohexylphenylethyl ketone, (4-
phenyl) phenylethyl ketone, 4-(2'-fluorophenoxy) phenylethyl ketone, 4-(1'cyclohexenyl) phenylethyl ketone, 6-methoxy-
Mention may be made of 2-naphthyl ethyl ketone and 4-(0-chlorophenylene-1-naphthyl ethyl ketone).

The basic reagent used in the method of the present invention includes:
Any substance that acts as a base in the reaction system may be used.
Among these, basic metals or basic metal compounds are preferred.

Particularly preferred are alkali metals, alkaline earth metals, or compounds of these metals, and particularly preferred are alkali metals or compounds thereof. Of these, potassium, sodium or lithium or their compounds are most preferred. The basic agent can be used in any form, including metals or various compounds.

In addition, the reagent may be soluble or insoluble in the reaction system, but soluble reagents are easier to operate, and the target compound can be obtained in high yield. Therefore, it is preferable. As specific examples of the form of the basic reagent, metals, oxides, alcoholades, substituted phenolades, hydrides, alkylated products, arylated products, amidated products, etc. are preferable, and it is possible to form the basic reagent in such a form within the reaction system. It may be a convertible compound.

In particular, it is preferably used as an alcoholade, a hydride, an alkylated product, or an arylated product, and most preferably as an alcoholade. When used as an alcoholade, a melon aliphatic monoaromatic alcohol can be used, but it is preferable to use a tertiary alcohol that is difficult to oxidize.

When alcohols are used as reaction solvents in carrying out the invention, it is advantageous to use alcoholades corresponding to the solvents as basic reagents. The basic reagent may be used in any proportion, but if the amount is too small, the conversion rate will be low, and if the amount used is increased, the reaction rate will be increased and the yield will be increased, but if the amount is too large, it will be uneconomical. brings no profit.

Generally, 0.01 to 80 per mole of ketone of the above formula u]
Moles, preferably in the range from 0.05 to 50 mol, particularly preferably from 0.1 to 40 mol, most advantageously from 0.2 to 30 mol. The method of the present invention is preferably carried out in the presence of a reaction solvent, and as such a reaction solvent, any solvent that does not react with the compounds represented by the general formulas [u] and [2] can be used. It is preferable to use a solvent that does not react with oxygen gas under these conditions. for example,
Alcohol, ether, aliphatic hydrocarbon, aromatic hydrocarbon, heterocyclic compound, sulfoxide, amide, or
It is preferable to use a mixed solvent consisting of two or more kinds of solvents. Such a solvent can also have any substituent that is stable in the reaction system. Suitable substituents include, for example, alkyl groups, allyl groups (Aryl), alkoxy groups, allyl groups (
Aryl)oxy group. Among them, tertiary alcohols such as tert-butyl alcohol, tert-amyl alcohol, amyl alcohol; ethers such as diethyl ether, dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diphenyl ether; such as petroleum ether, ligroin, hexane, heptane. Aliphatic hydrocarbons such as: For example, aromatic hydrocarbons such as benzene, triene, xylene, etc. are preferred;
It can also be used as a mixed solvent consisting of more than one species.
As a mixed solvent, any combination of two or more of the above solvents can be used; tertiary alcohol and aliphatic hydrocarbon or aromatic hydrocarbon; ether and aliphatic hydrocarbon or aromatic hydrocarbon; tertiary alcohol and ether. A combination of these is preferred.
To explain in more detail, when the reaction is carried out at a low temperature such as -100 or lower, for example, tert-butyl alcohol-
Toluene, tert-amyl alcohol-heptane, T
It is convenient to use a mixed solvent such as ertbutyl alcohol-diethyl ether. When the reaction solvent described above is used, the appropriate amount thereof is 1 to 1000 parts by weight, preferably 10 to 800 parts by weight, particularly preferably 20 to 600 parts by weight, per 1 part by weight of the ketone of formula u]. The most appropriate amount is 40 to 500 parts by weight.

In the reaction of the present invention, water is produced as the α-diketones of the above formula are produced, but it is desirable that the solvent used be as free of water as possible.

It is also possible to include a desiccant in the reaction system that does not adversely affect the reaction; examples of such desiccant include mirabilite,
Examples include magnesium sulfate. The molecular oxygen used in the present invention can be used as such, or can be diluted with an inert gas such as nitrogen, helium, argon, etc.

Industrially (it is convenient to use round oxygen gas or air), it is desirable to use molecular oxygen or molecular oxygen-containing gas after dehydration and drying. The temperature is more preferably 40°C or lower, and most preferably 0°C or lower.

As the reaction temperature decreases, the selectivity increases, but the lower limit is self-limited because the reaction rate decreases and the cost required for cooling increases. Generally, the lower limit is -70°C or higher, preferably -50°C or higher. To carry out the method of the present invention, a toxic or corrosive reagent can be removed by simply adding a compound represented by the general formula [0] and a basic phase to a solvent, and then introducing a molecular oxygen-containing gas. The compound represented by the general formula can be obtained without using anything else.

The α-diketones of general formula U can be easily extracted from the reaction solution thus obtained by, for example, the following operations.

For example, it can be extracted by adding water to the reaction solution and then extracting with a solvent that does not mix with water.

At this time, the basic reagent can be neutralized if necessary.
Alternatively, it can also be obtained by neutralizing a basic reagent and then distilling it under normal pressure or reduced pressure. Alternatively, the solution containing the compound represented by the general formula can be used as a starting material without being taken out. The method of the present invention will be explained below with reference to Examples.

All parts are by weight. Example 1 After 6 parts of metallic potassium was dissolved in 100 parts of tert-butyl alcohol, 1 part of 4-isobutylpropiophenone was added at 25°C, and oxygen gas was introduced while stirring vigorously.

After 25 minutes, the mixture was neutralized with diluted hydrochloric acid, extracted with ether, and distilled under reduced pressure to obtain 0.67 parts of 4-isobutylbenzoylmethylketone.

Example 2 After 2 parts of metallic sodium was dissolved in 200 parts of tert-butyl alcohol, 1 part of 4-isobutylpropiophenone was added at 20°C, and air was introduced for 25 minutes while stirring vigorously.

After neutralization with dilute hydrochloric acid, the mixture was extracted with ether and distilled under reduced pressure to obtain 0.36 parts of 4-isobutylbenzoylmethylketone and 0.65 parts of 4-isobutylpropiophenone.
Examples 3 to 7 Basicity listed in Tables 3 to 7? One part of 4-isobutylpropiophenone and oxygen gas were reacted using Compound 1 and a solvent at the reaction temperature and reaction time shown in the table.

Claims (1)

[Claims] 1. General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...[I] (In the formula, Ar is a substituted or unsubstituted aromatic hydrocarbon ring, R is an aliphatic group.) In the presence of a basic reagent, molecular oxygen or molecular General formula [II] characterized by reaction with oxygen-containing gas ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
... [II] (In the formula, Ar and R are the same as defined above.) A method for producing α-diketones.