JPH0798772B2 - Method for producing substituted acetophenone - Google Patents

Description

The present invention relates to a novel method for producing a substituted acetophenone. More specifically, the electron-withdrawing group was substituted
The present invention relates to a novel method for producing a substituted acetophenone by oxidizing a 1,1-diphenylethane-substituted product to obtain a corresponding peroxide, and then acid-decomposing it.

[Prior art and its problems] It is known to oxidize 1,1-diphenylethane with molecular oxygen under acidic conditions, but the products are complicated because they are oxidized under acidic conditions. I can't say.

Furthermore, it is not known to oxidize 1,1-diphenylethane substitution products obtained by substituting various substituents on the benzene nucleus of 1,1-diphenylethane with molecular oxygen.

The present inventors have studied that 1,1-diphenylethane substitution products in which various substituents are substituted on the benzene nucleus of 1,1-diphenylethane are oxidized by molecular oxygen under alkaline conditions and further decomposed under acidic conditions. As a result, it was surprisingly found that a substituted acetophenone is selectively obtained in the case of a specific substituent.

[Problems to be Solved by the Invention] That is, the present invention provides a 1,1-diphenylethane substituent substituted with an electron-withdrawing group at a temperature of 40 to 150 in the presence of a base.
Selective preparation of the substituted acetophenone substituted with the electron-withdrawing group, characterized in that the hydroperoxide corresponding to the substituent is obtained by oxidation with molecular oxygen at 0 ° C., and then the acid is decomposed with acid. It is about the method.

A preferred method is to oxidize a 1,1-diphenylethane substitution product represented by the following formula (I) with molecular oxygen to obtain a hydroperoxide represented by the following formula (II), which is then treated with an acid. The formula (II
It is a process for producing a substituted acetophenone represented by I).

In the above formula, R ₁ and R ₂ are the same electron-withdrawing group, or R ₁
Is a substituent having a higher degree of electron withdrawing than R ₂ . Further, m is an integer of 1 to 3, and n is an integer of 0 to 3.

The present invention will be further described below.

The substituted 1,1-diphenylethane represented by the above formula (I), which is a starting material used in the oxidation reaction which is the first step reaction of the present invention, has at least one electron-withdrawing group substituted. It is preferable. By doing so, the selectivity and yield of the substituted acetophenone are improved.

That is, the substituents that are substituted on the two benzene rings are
They may be the same or may be substituents having different electron withdrawing properties. By the oxidation and subsequent decomposition of peroxide, in the 1,1-diphenylethane substitution product of the raw material, the carbon / carbon bond of the benzene nucleus and the carbon atom substituted by the substituent having the higher electron donating property is cleaved, As a result, the substituted acetophenone substituted with the substituent having the higher electron withdrawing property is selectively produced.

The two substituents may be the same group, or their electron withdrawing properties may be different.
A -diphenylethane substitution product may be used as a raw material, or conversely, a 1,1-diphenylethane substitution product in which an electron-donating group is substituted may be used as a raw material. In addition, the electron-withdrawing group and the electron-donating group can be substituted with two phenyl groups of 1,1-diphenylethane, respectively, and this can be used as a raw material. In any case, according to the method of the present invention, a substituted acetophenone substituted with an electron-withdrawing group or a substituent having a higher electron-withdrawing property is selectively produced.

Representative electron withdrawing groups preferable in the present invention are halogen such as bromine, chlorine and iodine, nitro group, sulfone group, carboxyl group, alkoxycarbonyl group such as methoxycarbonyl and ethoxycarbonyl.

Examples of the electron-donating group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
Lower alkyl groups such as sec-butyl and pentyl, and carboxyl group-substituted alkyl groups in which these lower alkyl groups are substituted with a carboxyl group, such as carboxyethyl groups, and cyano groups in which these lower alkyl groups are substituted with a cyano group Substituted alkyl groups such as cyanoethyl groups, and alkoxycarbonylalkyl groups obtained by substituting these lower alkyl groups with alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, and lower alkoxy groups such as methoxy and ethoxy. These may substitute 1 to 3 in each benzene nucleus.

Further, R ₁ and R ₂ can be appropriately selected and combined from the above-mentioned electron-withdrawing group and electron-donating group.
Note that R ₂ may be a hydrogen atom.

Specific examples of the 1,1-diphenylethane substitution product of the above formula (I) include 1- (p-chlorophenyl) -phenylethane, 1-bromophenyl-1-phenylethane, 1-iodophenyl-1-phenylethane. , 1- (4-nitrophenyl) -1-phenylethane, 1- (4-carboxyphenyl) -1-phenylethane, 1- (2-carboxyphenyl) -1-phenylethane, 1- (2-ethoxycarbonyl) Phenyl) -1-phenylethane and the like are exemplified.

In the oxidation reaction of the present invention, the hydroperoxide represented by the above formula (II), which is a hydroperoxide corresponding to the above-mentioned starting material 1,1-diphenylethane, is obtained by oxidation with molecular oxygen.

For example, 1- (p-chlorophenyl) -1-phenylethane hydroperoxide, 1-bromophenyl-1-
Phenylethane hydroperoxide, iodophenyl-
1-phenylethane hydroperoxide, 1- (4-nitrophenyl) -1-phenylethane hydroperoxide, 1- (4-carboxyphenyl) -1-phenylethane hydroperoxide, 1- (2-carboxyphenyl) -1- Phenylethane hydroperoxide, 1-
Hydroperoxides such as (2-ethoxycarbonylphenyl) -1-phenylethane hydroperoxide are obtained.

Substituted acetophenone is then selectively produced by acidolysis of the above hydroperoxides. The substituted acetophenone selectively produced here is the raw material 1,1-
Among the substituents substituted on the diphenylethane substituent, the substituent having a higher degree of electron-withdrawing property is substituted.

Specific examples of the obtained substituted acetophenone of the formula (III) include 4-chloroacetophenone, 4-bromoacetophenone, 4-nitroacetophenone, 4-iodoacetophenone and 4-acetylbenzoic acid.

The molecular oxidation of the 1,1-diphenylethane substitution product which is the first step reaction of the present invention is carried out in the presence of a base. If this oxidation with molecular oxygen is carried out under acidic condition, the product becomes complicated and the production of the final target product, substituted acetophenone, is reduced, which is not preferable.

Chlorine is supplied to the reaction system in an amount of at least 0.06 gram equivalent with respect to 1 mol of the 1,1-diphenylethane substitution product as a starting material. Preferably 0.1 to 3.0, more preferably 0.
Feed 2-1.0 gram equivalents of base. The entire amount of the base to be present may be added to the reaction system before the start of the reaction, or may be divided and added to the reaction system. Preferably, it is divided into several parts, one of which is added to the reaction system before the start of the reaction, and the remaining part is added to the reaction system during the reaction.

Examples of the base include alkali metal compounds such as sodium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate: alkaline earth compounds such as calcium hydroxide, magnesium hydroxide and strontium hydroxide. A metal compound is preferably used. Two or more kinds of these bases can be used. As the base of the present invention, sodium hydroxide, sodium carbonate, potassium hydroxide and the like can be preferably used.

The oxidation reaction of the present invention is carried out in the presence of the above base, preferably in the presence of an aqueous medium. When carried out in the presence of an aqueous medium, the pH of the aqueous layer in the oxidation reaction is 7-14, preferably 8.5-10.5 due to the presence of the base. When the base is added to the system as an aqueous solution, the base is preferably added as an aqueous solution having a concentration of 0.1 to 2.5% by weight.

In the present invention, the oxidation reaction proceeds even without using a radical initiator, but the use of a radical initiator is preferable because the oxidation reaction becomes longer. It is sufficient to supply 0.001 to 0.1 mol of the radical initiator to the reaction system per mol of the 1,1-diphenylethane substitution product. If it is more than this, the reaction tends to runaway.

Here, the radical initiator refers to a compound that generates a radical under the adopted oxidizing conditions, and includes a —O—O— bond or a —
Includes compounds with N = N-bonds. Examples of such compounds include peroxides and azo compounds.

Specific radical initiators include hydrogen peroxide, ethyl peroxide, tert-butyl hydroperoxide, di-
tert-butyl peroxide, tert-butyl peroxybenzoate, tert-butyl peroxy-2-ethylhexanoate, tert-butyl peroxypivalate, 2-
Organic peroxides such as ethylhexanoyl peroxide, pivalyl peroxide, isooctyl peroxymonocarbonate, isoamyl peroxymonocarbonate, isooctyl peroxydicarbonate, isoamyl peroxydicarbonate, azobiscyclohexylcarbonitrile (ACN), azobisiso Butyronitrile,
Azobis-2,2-diphenylacetonitrile, 1-tert
-Butylazo-1-cyanocyclohexane, 2-tert-
Examples thereof include azo compounds such as butylazo-2-dianopropane and 2-tert-butylazo-2-cyanobutane.
These are appropriately mixed and used.

More preferable radical initiators are azo radical initiators such as azobiscyclohexylcarbonitrile (ACN).

The oxidation temperature is 40 to 150 ° C, preferably 70 to 110 ° C.
If the temperature is lower than this temperature, the reaction is remarkably slowed down, and if the temperature is higher than this temperature, the reaction recklessly occurs and the amount of by-products is increased. The reaction system is appropriately pressurized if necessary to maintain the liquid phase.

The oxidation method of the present invention is usually an aqueous phase containing a base and an organic phase containing a starting material 1,1-diphenylethane substitution product are mixed by mechanical stirring to obtain an emulsified state, in which state molecular oxygen is added. It is carried out by contacting with. The emulsified state can be formed by mechanically stirring and mixing the aqueous phase and the organic phase. At that time, emulsification can be facilitated by utilizing a conventionally known emulsifier. Generally, stronger stirring is more preferable. In addition, it is also possible to carry out the reaction only with the organic phase containing the 1,1-diphenylethane substitution product without using the aqueous phase.

Usually, the 1,1-diphenylethane-substituted product, which is the reaction raw material of the present invention, is lipophilic. Therefore, the reaction raw material is emulsified and reacted using an appropriate emulsifier which is inert to the reaction.
When the 1,1-diphenylethane-substituted product itself which is a reaction raw material is dissolved or dispersed in water, it is not necessary to use an emulsifier. The concentration of the 1,1-diphenylethane substitution product in water is not particularly limited, but is usually selected from the range of 0.05 to 0.4 g / ml. The concentration of the emulsifier for emulsifying the 1,1-diphenylethane-substituted product can be appropriately selected, but is usually about 0.1 to 0.5 g / 100 ml. Since the emulsifier is used under alkaline conditions, anionic or nonionic emulsifier is suitable.

For example, specifically, fatty acid soaps, N-acyl amino acids and salts thereof, alkyl ether carboxylates, carboxylates such as acylated peptides, alkylbenzene sulfonates, alkylnaphthalene sulfonates, dialkylsulfosuccinate ester salts, alkyls. Sulfoacetate,
Anionic surfactants such as sulfonates such as α-olefin sulfonate; ether type such as polyoxyethylene alkyl ether, ether ester type such as polyoxyethylene glycerin fatty acid ester, ester type such as polyethylene glycol fatty acid ester Examples include nonionic surfactants.

The organic phase may consist of the 1,1-diphenylethane substitution product itself as a starting material, or may appropriately contain an organic solvent.

Examples of the organic solvent include aromatic hydrocarbons substituted with secondary alkyl groups, benzene, halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons, saturated aliphatic hydrocarbons, alicyclic hydrocarbons, Examples include nitro compounds, nitriles and sulfoxides.

Specific examples of the aromatic hydrocarbon substituted with a secondary alkyl group include cumene, diisopropylbenzene, triisopropylbenzene, methylisopropylbenzene (cymene), fluoroisopropylbenzene, chloroisopropylbenzene, bromoisopropylbenzene, se
Alkylbenzenes such as c-butylbenzene, sec-butylbenzene, sec-hexylbenzene, biphenyls such as diisopropylbiphenyl, tetralins such as isopropyltetralin, and alkylnaphthalenes such as β-isopropylnaphthalene can be used. Among these, it is preferable to use isopropylbenzenes such as cumene, diisopropylbenzene, triisopropylbenzene, and halogenated isopropylbenzene.

Examples of halogenated aromatic hydrocarbons include chlorobenzene, dichlorobenzene, bromobenzene, dibromobenzene, fluorobenzene and difluorobenzene.

Examples of the halogenated aliphatic hydrocarbon include chloroform, carbon tetrachloride, dichloroethane and trichloroethane.

Examples of the aliphatic hydrocarbon include hexane, heptane, octane, nonane, decane, undecane, dodecane and the like.

Examples of the aliphatic hydrocarbon include cyclohexane, cycloheptane, chlorocyclohexane, dichlorohexane and the like.

Examples of the nitro compound include nitrobenzene and nitromethane.

Examples of nitriles include benzonitrile and acetonitrile.

Examples of sulfoxides include dimethyl sulfoxide, dimethyl sulfone, and tetramethylene sulfone (sulfolane).

Among these organic solvents, it is preferable to use halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, from the viewpoints of easy availability of the solvent and post-treatment after the reaction. The amount of the organic solvent used is preferably 20 to 1000 parts by weight, preferably 50 to 300 parts by weight, per 100 parts by weight of the 1,1-diphenylethane-substituted compound as a reaction raw material.

As the molecular oxygen, pure oxygen may be used, or a mixed gas with an inert gas such as nitrogen, for example, air can be used. The supply amount of molecular oxygen is not particularly limited, and it is sufficient to supply a sufficient amount for oxidation. Usually, it is in the range of 5 to 15 Nl / hour in terms of oxygen gas per 100 g of the charged 1,1-diphenylethane substitution product for the oxidation reaction.

The reaction time of the first-stage oxidation reaction is not particularly limited,
It is appropriately selected from the range of several tens of hours.

By the first-stage oxidation reaction of the present invention, the hydroperoxide represented by the above formula (II) corresponding to the 1,1-diphenylethane-substituted product of the reaction raw material can be obtained. Since these hydroperoxides are usually relatively stable, after completion of the reaction, they are separated by distillation, or the organic phase is added to an aqueous solution of 20 to 40% by weight of sodium hydroxide to precipitate the sodium salt of hydroperoxide. It is also possible to recover the hydroperoxide by isolating. However, it is usually preferable to adjust the concentration of hydroperoxide appropriately while being dissolved in an organic solvent, and then subject this to the subsequent acid decomposition step. For that purpose, stirring is usually stopped after the oxidation reaction, and the reaction phase is allowed to stand to separate into an organic phase containing hydroperoxide and an aqueous phase. Then the aqueous phase is removed and the organic phase is recovered, which is then subjected to an acid decomposition step. Alternatively, it can be subjected to the next acid decomposition step without separation into two phases, an organic phase and an aqueous phase.

The acid decomposition of the present invention is carried out in the presence of an acidic catalyst. Examples of acidic catalysts include inorganic acids such as sulfuric acid, hydrochloric acid, perchloric acid and phosphoric acid, organic acids such as chloroacetic acid and paratoluene sulfonic acid, cation exchange resins, solid inorganic acids such as silica alumina and silica titania, and organic acids. Is used. When using an inorganic acid or an organic acid as the acidic catalyst, it is preferable to use a solvent in order to avoid the risk associated with the decomposition reaction. For example, ketones such as acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone,
It is preferable to use organic acids such as acetic acid, water and the like.

The reaction temperature for acid decomposition is usually 30 to 150 ° C., preferably 40 to 9
Perform in the range of 0 ℃. If the temperature is out of this range, the yield of the target compound will decrease, which is not preferable. The reaction time for acid decomposition is not particularly limited, but usually it can be carried out within the range of several minutes to several hours.

After the acid decomposition is completed, the substituted acetophenone represented by the formula (III), which is the target compound, is recovered from the acid decomposition mixture. As a recovery method, when an inorganic acid or an organic acid is used as the acidic catalyst, the acid decomposition mixture is extracted and separated by adding an extraction solvent such as diethyl ether, and then the solvent is distilled off and further distilled. Alternatively, the substituted acetophenone can be recovered by crystallization or the like.

When a solid acid is used as the acidic catalyst, the solid acid catalyst is removed from the acid decomposition mixture by filtration or the like, and then the substituted acetophenone is recovered as described above.

[Effect of the Invention] According to the method of the present invention, a substituted acetophenone can be produced from a 1,1-diphenylethane-substituted product with high selectivity or yield. That is, the substituted acetophenone is selectively produced and obtained in a high yield because the 1,1-diphenylethane-substituted product of the starting material has an electron-withdrawing group.

[Examples] The present invention is described in detail below with reference to Examples.

Example 1 11.4 g (52.8 mmol) of 1,1- (4-chlorophenyl) -1-phenylethane as a 1,1-diphenylethane substitution product,
A mixture of 0.04 g of sodium stearate, 0.7 g of azobiscyclohexylcarbonitrile (ACN) as a reaction initiator and 30 ml of a 1% sodium carbonate aqueous solution was vigorously stirred at 85 ° C, and pure oxygen was added at a rate of 4 l / hr for 10 hours. Introduced. Then, after cooling to room temperature, when the peroxide concentration of the reaction solution was measured by iodometry, the reaction rate was 25.0%.

Of the peroxide solution thus obtained, 2 ml was added to 25 ml of a 1: 1 mixture of glacial acetic acid and 10% sulfuric acid aqueous solution, and the mixture was stirred at 50 ° C. for 4 hours.

When the product was analyzed by gas chromatography and mass spectrum, the selectivity of 4-chloroacetophenone among the acetophenones in the reaction product was 65.4%, whereas that of unsubstituted acetophenone was only 34.6%.

Examples 2 to 4 Reactions were carried out in the same manner as in Example 1 using the various substrates shown in Table 1.

The results are also shown in Table 1.

Example 5 11.9 g (52.8 mm) of 1- (4-carboxylphenyl) -1-phenylethane as 1,1-diphenylethane substitution product
ol), 0.04 g of sodium stearate, 2.1 g of sodium hydroxide, 0.7 g of azobiscyclohexylcarbonitrile (ACN) as a reaction initiator, and 30 ml of a 1% sodium carbonate aqueous solution at 85 ° C. with vigorous stirring. Oxygen was introduced at a rate of 4 l / hr for 10 hours. Aqueous sodium carbonate solution was added to prevent the reaction solution from becoming acidic as the reaction progressed.

The hydroperoxide-containing solution thus obtained was cooled to room temperature, acidified with sulfuric acid, and extracted with ether. When the hydroperoxide concentration in the ether layer was measured by iodometry, the reaction rate was 13%.

10% sulfuric acid aqueous solution was added to the residue after removing ether by distillation.
0 ml was added and the mixture was heated at reflux concentration for 4 hours with stirring.

After cooling to room temperature, it was extracted with ether. The ether layer was dried over magnesium sulfate and then the ether was removed by distillation. 50 ml of a methanol solution containing 5% sulfuric acid in the residue
The mixture was heated at reflux temperature for 4 hours. After neutralizing the product,
The oil was extracted with ether, the ether was removed by distillation, and the residue was analyzed by gas chromatography and mass spectrum. As a result, 4 out of the acetophenones in the reaction product were found.
The selectivity for methyl acetylbenzoate was 98.4%, whereas that for unsubstituted acetophenone was only 1.6%.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07C 201/12 205/45 // B01J 23/02 27/232 C07B 61/00 300 C07C 409/08

Claims (3)

[Claims] 1. At least one electron-withdrawing group is substituted
Oxidation of a 1,1-diphenylethane substituent with molecular oxygen in the presence of a base at a temperature of 40 to 150 ° C. to give a hydroperoxide corresponding to the substituent, which is then acid decomposed. A method for selectively producing a substituted acetophenone in which the electron-withdrawing group is substituted. 2. A 1,1-diphenylethane-substituted compound represented by the following formula (I) is oxidized with molecular oxygen to obtain the following formula (I
A method for producing a substituted acetophenone represented by the following formula (III), characterized in that a hydroperoxide represented by I) is obtained, and then this is acid-decomposed. In the above formula, R ₁ and R ₂ are the same electron-withdrawing substituent, or R ₁ is a substituent having a relatively higher degree of electron-withdrawing than R ₂ . Further, m is an integer of 1 to 3, and n is an integer of 0 to 3. 3. The method for producing a substituted acetophenone according to claim 2, wherein R ₁ is a halogen atom.