JPH09188647A - Method for producing acetophenones - Google Patents

Abstract

(57) [Abstract] [PROBLEMS] To provide a method for producing acetophenones, which are intermediates for pharmaceuticals and agricultural chemicals. SOLUTION: The following general formula (I): (In the formula, R ¹ and R ² each independently represent H, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, provided that R ¹ and R ² are not H at the same time.) By reacting 1-substituted phenylethanols with bromine, the following general formula (II): (In the formula, R ¹ and R ² are as defined above, and R ³ is a methyl group or a bromomethyl group.), And acetophenones are produced.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing acetophenones useful as intermediates for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art
Acetophenones can be produced by a Friedel-Crafts reaction of substituted benzenes and acetyl chloride (S
synthesis, 672 (197)), a method of oxidizing ethylbenzenes or 1-substituted phenylethanols with peroxides or metal oxides (J. Am. Chem.
Soc. , 69, 576 (1947)), etc., but these production methods have problems such as regioselectivity in Friedel-Crafts reaction, use of peroxides and heavy metals, and other industrially useful methods. It was desired to develop a new manufacturing method.

[0003]

Means for Solving the Problems As a result of intensive studies for solving the above-mentioned problems, the present inventors have found that 1-substituted phenylethanols, α-bromoethylbenzenes or bromoethylbenzenes are reacted with bromine, The present invention has been completed by finding that acetophenones or α-bromoacetophenones can be obtained in high yield.

That is, the gist of the present invention is the following general formula (I)

[0005]

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(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group. Provided that R ¹ and R ² are simultaneously a hydrogen atom. Bromine is allowed to act on 1-substituted phenylethanols represented by the following general formula (II)

[0007]

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(In the formula, R ¹ and R ² are as defined above, and R ³ is a methyl group or a bromomethyl group.)
A method for producing acetophenones, which comprises obtaining acetophenones represented by: And the following general formula (III)

[0009]

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(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group. Provided that R ¹ and R ² are simultaneously a hydrogen atom. ), Α-bromoethylbenzenes represented by the following general formula (II) by reacting bromine in the presence of at least one of a base and a phase transfer catalyst and water.

[0011]

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(In the formula, R ¹ and R ² are as defined above, and R ³ is a methyl group or a bromomethyl group.)
A method for producing acetophenones, which comprises obtaining acetophenones represented by: Furthermore, the following general formula (IV)

[0013]

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(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group. Provided that R ¹ and R ² are simultaneously a hydrogen atom. Excluding)) to the ethylbenzenes represented by
In the presence of at least one of a base and a phase transfer catalyst and water, bromine is allowed to act on the following general formula (II)

[0015]

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(In the formula, R ¹ and R ² are as defined above, and R ³ is a methyl group or a bromomethyl group.)
The method for producing acetophenones is characterized by obtaining acetophenones represented by

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred specific embodiments of the present invention will be described below. As the 1-substituted phenylethanols of the general formula (I), the α-bromoethylbenzenes of the general formula (III) or the ethylbenzenes of the general formula (IV), R ¹ and R ² are both halogen atoms. Examples thereof include a fluorine atom, a chlorine atom and a bromine atom.

The acetophenones of the general formula (II) can be produced by reacting the 1-substituted phenylethanols of the general formula (I) with bromine. Specific examples of the 1-substituted phenylethanols of the general formula (I) used in the present invention include 3-chlorophenylethanol, 3-bromophenylethanol, 3-trifluoromethylphenylethanol, 3,5-dichlorophenylethanol, 3-Bromo-5-chlorophenylethanol, 3-chloro-5-
Nitrophenyl ethanol, 3-nitrophenyl ethanol, 4-cyanophenyl ethanol, 2-cyano-4
-Nitrophenyl ethanol and the like can be mentioned.

Further, the 1-substituted phenylethanols of the above-mentioned general formula (I) used in the present invention include a part of the novel compound, but can be easily synthesized by hydrolyzing α-haloethylbenzenes, for example. You can In the present invention, bromine is added in an amount of 0.5 to 1-substituted phenylethanols of the above general formula (I) from the viewpoint of reaction yield.
To 1.5 equivalents, preferably 0.8 to 1.2 equivalents, 3
Add dropwise to the reaction system over 0 minutes to 2 hours.

This reaction is carried out without solvent or by diluting with an appropriate organic solvent. The organic solvent used in the reaction, carbon tetrachloride, chloroform, a halogen-based solvent such as dichloromethane, benzene, cyclohexane, hexane,
Hydrocarbon solvents such as heptane, ether solvents such as diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethoxyethane, alcohol solvents such as methanol, ethanol and propanol, and water solvents are preferably used. The amount of the solvent used is not particularly limited, but may be the above general formula (I).
It is used in an amount of 0 to 100 times by weight, preferably 0 to 20 times by weight, based on 1-substituted phenylethanols.

The reaction temperature is −20 to 150 ° C., preferably 0 to 100 ° C., and the reaction is carried out for 1 to 10 hours. In the above reaction, acetophenones of the above general formula (II) in which R ³ is a methyl group are obtained. Specifically, 3-chloroacetophenone, 3-bromoacetophenone, 3-trifluoromethylacetophenone, 3,5-dichloroacetophenone, 3-bromo-5-chloroacetophenone, 3-chloro-5-nitroacetophenone, 3-nitroacetophenone, 4-cyanoacetophenone, 2-cyano-4-nitroacetophenone and the like can be mentioned.

Further, 1 of the general formula (I) described above
In the reaction for producing acetophenones of the general formula (II) in which R ³ is a methyl group from -substituted phenylethanol, bromine is added in an amount of 1.5 to 2 with respect to the 1-substituted phenylethanols of the general formula (I). .5 equivalents, preferably 1.
When it is carried out under similar reaction conditions except that 8 to 2.2 equivalents are used and the solution is added dropwise over 1 to 3 hours, α-bromo, which is an acetophenone of the above general formula (II) in which R ³ is a bromomethyl group. Acetophenones are obtained. Specifically 3
-Chloro-α-bromoacetophenone, 3-bromo-α
-Bromoacetophenone, 3-trifluoromethyl-α
-Bromoacetophenone, 3,5-dichloro-α-bromoacetophenone, 3-bromo-5-chloro-α-bromoacetophenone, 3-chloro-5-nitro-α-bromoacetophenone, 3-nitro-α-bromoacetophenone, 4-cyano-α-bromoacetophenone, 2-cyano-4-nitro-α-bromoacetophenone and the like can be mentioned.

The acetophenones of the general formula (II) are obtained by reacting the α-bromoethylbenzenes of the general formula (III) with bromine in the presence of at least one of a base and a phase transfer catalyst and water. Can be manufactured. Specific examples of the α-bromoethylbenzenes of the general formula (III) used in the present invention include 3-chloro-α-bromoethylbenzene, 3-bromo-α-bromoethylbenzene,
3-trifluoromethyl-α-bromoethylbenzene,
3,5-Dichloro-α-bromoethylbenzene, 3-bromo-5-chloro-α-bromoethylbenzene, 3-chloro-5-nitro-α-bromoethylbenzene, 3-nitro-α-bromoethylbenzene, 4-cyano- Examples include α-bromoethylbenzene and 2-cyano-4-nitro-α-bromoethylbenzene.

In this reaction, bromine is used in an amount of 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, relative to the α-bromoethylbenzenes of the above general formula (III), from the viewpoint of reaction yield. Add dropwise over 30 minutes to 2 hours. The solvent used in this reaction is, for example, an aqueous solvent or α-of the general formula (III).
It is carried out in a mixed solvent system with water and an organic solvent in an amount equal to or more than the equivalent of bromoethylbenzenes.

Examples of the organic solvent used in the reaction include halogen solvents such as carbon tetrachloride, chloroform and dichloromethane; hydrocarbon solvents such as benzene, cyclohexane, hexane and heptane; diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ether solvent such as diethoxyethane; methanol,
An alcohol solvent such as ethanol is preferably used.
The amount of the organic solvent to be mixed with water is not particularly limited, but it is used in an amount of 0 to 100 times by weight, preferably 0 to 20 times by weight, of the α-bromoethylbenzenes of the general formula (III).

In this reaction, a base and a phase transfer catalyst are used alone or in combination. Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, and triethylamine, pyridine, dimethylaminopyridine, collidine, DBU.
(1,8-diazobicyclo (5,4,0) undec-7
-Ene), DBN (1,5-diazobicyclo (4,3,
0) Organic bases such as nona-5-ene) and the like. The amount of the base used is not particularly limited, but 0.001 to 10 equivalents, preferably 0.01 to 1.0 equivalents relative to the α-bromoethylbenzenes of the general formula (III) are used. good.

As the phase transfer catalyst used in this reaction, onium salts such as quaternary phosphonium salts and quaternary ammonium salts and crown compounds are used, and preferably quaternary ammonium salts are used. Specifically, 4
Examples of the quaternary phosphonium salts include tetraethylphosphonium chloride, tetraethylphosphonium bromide, tetraethylphosphonium iodide, tetrabutylphosphonium bromide, triphenylbenzylphosphonium bromide, tetraphenylphosphonium bromide, and the like. Tetramethylammonium, tetraethylammonium hydroxide, trimethylbenzylammonium hydroxide, tetramethylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, triethylbenzylammonium bromide, trimethylphenylammonium bromide, triethylbenzylammonium chloride, chloride Tetramethylammonium, trioctylmethylammonium chloride, tributylbenzylammonium chloride, trichloride Chill benzyl ammonium chloride N
-Laurylpyridinium chloride, N-benzylpicolinium chloride, N-lauryl-4-picolinium chloride, N-laurylpicolinium chloride, aliquat336 (tricaprylmethylammonium chloride), tetramethylammonium iodide, tetra-n-butylammonium iodide,
Tetrabutylammonium hydrogensulfate and the like can be mentioned, and as the crown compound, crown ethers such as 15-crown-5 and 18-crown-6, cryptands, spherands, and polyethylene glycol exhibiting similar effects can be mentioned. .

The amount of the phase transfer catalyst used is not particularly limited, but is 0.001 to 1.0 equivalent, preferably 0.005 to 1.0 equivalent to the α-bromoethylbenzenes of the general formula (III). It is better to use 0.5 equivalent. The reaction temperature is −20 to 150 ° C., preferably 0 to 100 ° C. and 30
React for 10 minutes.

In the above reaction, acetophenones of the above general formula (II) in which R ³ is a methyl group are obtained. Further, the above general formula (III) in the above general formulas α- bromoethylbenzene such that R ³ is a methyl group, wherein (I
In the reaction for producing acetophenones of I), bromine is 1.5 to 2.5 equivalents, preferably 1.8 to 2.2, based on the α-bromoethylbenzenes of the general formula (III).
When it is carried out under similar reaction conditions except that the reaction mixture is used in an equivalent amount and added dropwise over 1 to 3 hours, α-bromoacetophenones which are acetophenones of the general formula (II) in which R ³ is a bromomethyl group are obtained. .

Further, the acetophenones of the general formula (II) can be produced by reacting ethylbenzenes of the general formula (IV) with bromine in the presence of at least one of a base and a phase transfer catalyst and water. . Specific examples of the ethylbenzenes of the general formula (IV) used in the present invention include 3-chloro-ethylbenzene, 3-bromo-ethylbenzene, 3-trifluoromethyl-ethylbenzene,
3,5-dichloro-ethylbenzene, 3-bromo-5-
Examples thereof include chloro-ethylbenzene, 3-chloro-5-nitro-ethylbenzene, 3-nitro-ethylbenzene, 4-cyano-ethylbenzene, 2-cyano-4-nitro-ethylbenzene and the like.

In the present reaction, bromine is added to the ethylbenzenes of the general formula (IV) in the range of 1.5-2.
5 equivalents, preferably 1.8 to 2.2 equivalents, are added dropwise over 1 to 3 hours. As the solvent used in this reaction,
It is carried out in a water solvent or a mixed solvent system with water and an organic solvent in an amount equal to or more than the equivalent of α-bromoethylbenzenes. Examples of the solvent used in the reaction include halogen solvents such as carbon tetrachloride, chloroform and dichloromethane; hydrocarbon solvents such as benzene, cyclohexane, hexane and heptane; diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethoxyethane and the like. Ether solvents; alcohol solvents such as methanol and ethanol are preferably used. The amount of the organic solvent to be mixed with water is not particularly limited, but it is 0 to 100 times by weight, preferably 0 to 100 times the amount of the ethylbenzenes represented by the general formula (IV).
It is used in an amount of 20 times the weight.

In this reaction, the base and the phase transfer catalyst are used alone or in combination. The type and amount of the base or phase transfer catalyst used in this reaction are those represented by the general formula (II
I) from the α-bromoethylbenzenes of the general formula (I
It can be carried out under the same conditions as in the case of the production method of acetophenones of I). The reaction temperature is −20 to 150 ° C., preferably 0 to 100 ° C., and the reaction is carried out for 1 to 15 hours.

In the above reaction, acetophenones of the above general formula (II) in which R ³ is a methyl group are obtained. Further, in the reaction for producing the acetophenones of the general formula (II) in which R ³ is a methyl group from the ethylbenzenes of the general formula (IV) described above, bromine is converted to the ethylbenzenes of the general formula (IV). On the other hand, when 2.5 to 3.5 equivalents, preferably 2.8 to 3.2 equivalents are used and the reaction is carried out under the same reaction conditions except that the dropwise addition is performed over 1 to 4 hours, R ³ is a bromomethyl group. [Alpha] -Bromoacetophenones which are acetophenones of the above general formula (II) are obtained.

In any reaction of the present invention for producing the acetophenones of the above general formula (II), after the reaction,
The acetophenones can be isolated by washing with an aqueous alkali solution, extracting with an organic solvent and concentrating. Further, if necessary, the product can be purified by performing operations such as recrystallization, distillation and column chromatography.

[0035]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded. <Example 1> Synthesis of m-chloroacetophenone To 4.0 g of m-chloroethylbenzene, 0.4 g of benzyltrimethylammonium bromide and 4 ml of water were added,
With stirring at room temperature, 9.6 g of bromine was added dropwise over 1 hour.
After the dropping was completed, the reaction was further continued at room temperature for 2 hours to complete the reaction. After completion of the reaction, the reaction mixture was diluted with ether, washed with 10% aqueous sodium hydroxide solution and saturated brine, and the ether layer was dried over anhydrous sodium sulfate and concentrated to obtain 3.4 g of m-chloroacetophenone (as a pure component). . The yield was 84% with respect to m-chloroethylbenzene. <Example 2> Synthesis of α-bromo-m-chloroacetophenone To 4.0 g of m-chloroethylbenzene, 0.4 g of benzyltrimethylammonium bromide and 4 ml of water were added,
With stirring at room temperature, 14.1 g of bromine was added dropwise over 2 hours. After the dropping was completed, the reaction was further continued at room temperature for 4 hours to complete the reaction. After completion of the reaction, the reaction mixture was diluted with ether, washed with 10% aqueous sodium hydroxide solution and saturated saline, and the ether layer was dried over anhydrous sodium sulfate and concentrated.
5.8 g (as pure content) of -bromo-m-chloroacetophenone was obtained. The yield was 88% with respect to m-chloroethylbenzene.

[0036]

EFFECT OF THE INVENTION By reacting 1-substituted phenylethanols, α-bromoethylbenzenes or bromoethylbenzenes with bromine, acetophenones or 1-bromoethylbenzenes
Substituted phenylethanols are obtained in high yield.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07C 49/807 9049-4H C07C 49/807 201/12 9450-4H 201/12 205/45 9450- 4H 205/45 253/30 8927-4H 253/30 255/56 8927-4H 255/56 // C07B 61/00 300 C07B 61/00 300

Claims (5)

[Claims] 1. A compound represented by the following general formula (I) (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, provided that R ¹ and R ² are not simultaneously hydrogen atoms.) By reacting 1-substituted phenylethanols represented by bromine with bromine, the following general formula (II): (Wherein R ¹ and R ² are as defined above, and R ³
Represents a methyl group or a bromomethyl group. ) The method for producing acetophenones, which comprises obtaining acetophenones represented by 2. The following general formula (III): (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, provided that R ¹ and R ² are not simultaneously hydrogen atoms.) The α-bromoethylbenzenes represented by the following general formula (II) embedded image is prepared by reacting bromine with at least one of a base and a phase transfer catalyst and water. (Wherein R ¹ and R ² are as defined above, and R ³
Represents a methyl group or a bromomethyl group. ) The method for producing acetophenones, which comprises obtaining acetophenones represented by 3. The following general formula (IV): (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, provided that R ¹ and R ² are not simultaneously hydrogen atoms.) By reacting ethylbenzenes represented by with bromine in the presence of at least one of a base and a phase transfer catalyst and water, the following general formula (II) (Wherein R ¹ and R ² are as defined above, and R ³
Represents a methyl group or a bromomethyl group. ) The method for producing acetophenones, which comprises obtaining acetophenones represented by 4. The method according to claim 1, wherein an alkali metal hydroxide or an alkali metal salt is used as the base. 5. The method according to claim 1, wherein a quaternary ammonium salt is used as the phase transfer catalyst.