JP2019104702A - Method for producing a 3'-trifluoromethyl group-substituted aromatic ketone - Google Patents

Abstract

To provide a method for producing a 3'-trifluoromethyl group-substituted aromatic ketone that uses an inexpensive and easily available raw material and is industrially excellent with high production efficiency.SOLUTION: A 3-halogen-substituted benzotrifluoride compound is reacted with a magnesium metal in the presence of a lithium chloride of 1.0 mol or more times higher than the 3-halogen-substituted benzotrifluoride compound, to convert it to a Grignard reagent, and the Grignard reagent is reacted with an acid anhydride at a reaction temperature of 0°C or less and then hydrolyzed, thereby producing 3'-trifluoromethyl group-substituted aromatic ketone.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing 3 '-trifluoromethyl group substituted aromatic ketone. In particular, the present invention relates to a method for producing industrially superior 3 '-trifluoromethyl group-substituted aromatic ketone.

  The 3'-trifluoromethyl group-substituted aromatic ketone is a compound useful as a fine chemical, a medical and agrochemical raw material, a resin / plastics raw material, an electronic information material, an optical material, and the like. The 3 '-trifluoromethyl group substituted aromatic ketones are useful in a wide variety of industrial applications.

  As a method for producing a 3'-trifluoromethyl group-substituted aromatic ketone, in Patent Document 1, 3-bromobenzotrifluoride is subjected to Grignard exchange with isopropyl magnesium bromide to form 3-trifluoromethylbenzyl magnesium bromide After that, it is reacted with acetic anhydride and hydrolyzed to form 3'-trifluoromethylacetophenone.

  However, in the method described in Patent Document 1, since dilute isopropyl magnesium bromide is used, the concentration of the obtained Grignard reagent is also dilute, and the productivity is not high.

  In Patent Document 2, a 3-bromobenzotrifluoride compound is reacted with magnesium metal in the presence of 0.25 mol times of lithium chloride (LiCl) to convert it into a Grignard reagent, and the Grignard reagent is reacted with an acid anhydride at a reaction temperature After reaction at 20-30 ° C., hydrolysis treatment is performed to generate 3'-trifluoromethylacetophenone.

  However, in the method described in Patent Document 2, the yield of 3'-trifluoromethylacetophenone was as low as 38.1% (based on the starting material m-bromobenzotrifluoride).

  There is a problem in industrially using the method for producing these 3'-trifluoromethyl group-substituted aromatic ketones described above, and an inexpensive method for producing 3'-trifluoromethyl group-substituted aromatic ketone is desired. The

Chinese Patent Application Publication No. 105461538 International Publication No. 2016/043079

  An object of the present invention is to provide a method for producing an industrially superior 3 '-trifluoromethyl group-substituted aromatic ketone which uses inexpensive and easily available raw materials and has high production efficiency.

（但し、Ｘは、ＣｌまたはＢｒである）
１．０モル倍以上の塩化リチウムの存在下、マグネシウム金属と反応させて、グリニャール試薬に転化し、該グリニヤール試薬を酸無水物とを反応温度０℃以下で反応させた後、加水分解処理して、下記一般式で示される３’-トリフルオロメチル基置換芳香族ケトンを製造する３’-トリフルオロメチル基置換芳香族ケトンの製造方法である。

（但し、ｎは、１〜４の整数である） The present invention relates to a 3-halogen substituted benzotrifluoride compound represented by the following general formula

(Where X is Cl or Br)
It is reacted with magnesium metal in the presence of 1.0 or more moles of lithium chloride to convert it to a Grignard reagent, and the Grignard reagent is reacted with an acid anhydride at a reaction temperature of 0 ° C. or less and then subjected to hydrolysis treatment It is a method for producing a 3'-trifluoromethyl group-substituted aromatic ketone which produces a 3'-trifluoromethyl group-substituted aromatic ketone represented by the following general formula.

(Where n is an integer from 1 to 4)

  The method for producing a 3'-trifluoromethyl group-substituted aromatic ketone according to the present invention does not use expensive raw materials, and the presence of 1.0 mole or more of lithium chloride relative to the 3-halogen-substituted benzotrifluoride compound Below, a Grignard reagent is produced as an intermediate, and by efficiently reacting this Grignard reagent with an acid anhydride at a reaction temperature of 0 ° C. or less, the yield of a 3′-trifluoromethyl group-substituted aromatic ketone is unexpectedly high. It can be manufactured at a rate. The method for producing the 3 '-trifluoromethyl group-substituted aromatic ketone of the present invention is an industrially excellent production method.

  The 3'-trifluoromethyl group-substituted aromatic ketone produced by the method for producing a 3'-trifluoromethyl group-substituted aromatic ketone of the present invention is a fine chemical, a medical and agricultural chemical raw material, a resin / plastics raw material, an electronic information material, an optical information material It can be used as a material or the like.

The details of the present invention will be described below.
The method for producing a 3'-trifluoromethyl group-substituted aromatic ketone of the present invention uses a 3-halogen-substituted benzotrifluoride compound represented by the following general formula as a starting substrate.

（但し、Ｘは、ＣｌまたはＢｒである）

(Where X is Cl or Br)

  Specific examples of the 3-halogen substituted benzotrifluoride compound are m-chlorobenzotrifluoride and m-bromobenzotrifluoride.

  In the present invention, a Grignard reagent is produced by reacting a halogen atom of a 3-halogen-substituted benzotrifluoride compound with magnesium metal in the presence of lithium chloride in an amount of 1.0 mol times or more with respect to the 3-halogen-substituted benzotrifluoride compound. Convert to The conversion reaction to the Grignard reagent can utilize known conversion reactions.

  In the present invention, as the magnesium metal to be used, chips, ribbons and powders can be used, but in terms of handling, chips are preferable.

  In the present invention, the amount of magnesium metal used is preferably 0.8 to 3 mol and more preferably 1.0 to 1.5 mol per mol of the starting 3-halogen-substituted benzotrifluoride compound.

  In the present invention, it is preferable to add iodine, bromine or an inexpensive compound containing these in order to obtain a surface oxide film of magnesium metal and to enhance the reactivity. Preferred examples of such compounds include methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like.

  In the present invention, the reaction to convert to a Grignard reagent is carried out in a dehydrated system. For this reason, the reaction may use a previously dehydrated solvent, or may add an inexpensive Grignard reagent to the solvent before the reaction to remove water contained in the solvent.

  As the solvent used in the preparation of the Grignard reagent of the present invention, a solvent capable of efficiently advancing the reaction is used. The solvent used in the preparation of the Grignard reagent is preferably an ether-based solvent which easily generates the Grignard reagent. Specific examples of the solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dioxane, 1,4-dioxane, cyclopropyl methyl ether And methyl-tertiary butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, benzene, toluene, xylene and the like. Among them, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, cyclopropyl methyl ether and methyl-tert-butyl ether are preferable.

  The amount of the solvent used is preferably determined according to the solubility of the 3-halogen substituted benzotrifluoride compound or the Grignard reagent, the slurry concentration, or the properties of the reaction solution. The amount of the solvent used is preferably 1 to 100 times by mole, more preferably 3 to 20 times by mole, the amount of the 3-halogen-substituted benzotrifluoride compound. If it is less than 1 mole, the yield of the Grignard reagent may be lowered, and if it is more than 100 moles, the productivity may be deteriorated, which may result in an uneconomical process.

  In the preparation of the Grignard reagent of the present invention, a 3-halogen substituted benzotrifluoride compound is reacted with magnesium metal and converted to a Grignard reagent, in an amount of 1.0 mole times or more based on the 3-halogen substituted benzotrifluoride compound Lithium chloride (LiCl) coexists. By coexisting 1.0 mol times or more of LiCl with respect to the 3-halogen substituted benzotrifluoride compound, the formation of the Grignard reagent rapidly occurs, and the subsequent reaction with the acid anhydride is in high yield. It is to happen.

  In the present invention, the amount of LiCl used is at least 1.0 molar times with respect to the 3-halogen substituted benzotrifluoride compound. Preferably, it is a 1.0 to 3.0 molar amount. When the amount of LiCl is 1.0 to 3.0 mol times the amount of the 3-halogen substituted benzotrifluoride compound, the formation of the Grignard reagent occurs more rapidly, and the LiCl dissolves completely in the reaction system.

  Specific examples of the acid anhydride to be reacted with the Grignard reagent in the production method of the present invention include acetic anhydride, propionic anhydride, butyric anhydride and valeric anhydride. The acid anhydride is preferably acetic anhydride, propionic anhydride or butyric anhydride.

  The amount of the acid anhydride used is preferably 0.5 to 10 moles, more preferably 1 to 5 moles, per mole of the 3-halogen-substituted benzotrifluoride compound. It is. If the amount is less than 0.5 molar volume, unreacted Grignard reagent may remain, the yield may decrease, and load may occur in isolation and purification of the desired product. If the amount is more than 10 molar times, unreacted acid anhydride may remain and productivity may deteriorate, and the load on separation of unreacted acid anhydride and 3'-trifluoromethyl group-substituted aromatic ketone is large. May be

  In the present invention, the reaction of the Grignard reagent and the acid anhydride may use a solvent. The solvent is preferably a solvent that does not inhibit the reaction and can be efficiently advanced. Specific examples of the solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dioxane, 1,4-dioxane, cyclopropyl methyl ether And methyl-tertiary butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, benzene, toluene, xylene and the like. Among them, tetrahydrofuran, 1,3-dioxane, cyclopropyl methyl ether, benzene, toluene and xylene are preferred. It is mesitylene.

  The amount of the solvent used is preferably 0.05 to 50 times by weight, more preferably 0.5 to 5 times by weight, relative to the 3 '-trifluoromethyl group-substituted aromatic ketone. If the amount of the solvent used is 0.05 weight times or less, it is difficult to remove the heat of reaction and the reaction may run away. If it is more than 50 times by weight, productivity may be bad.

  In the reaction method of a Grignard reagent and an acid anhydride, a solution containing an acid anhydride may be put into a Grignard reagent solution, or a Grignard reagent solution may be put into a solution containing an acid anhydride. In order to prevent a sudden exothermic reaction or reaction runaway, the solution to be introduced is introduced continuously or in a divided manner over time, such as intermittently inserted, and controlled so that the temperature in the reaction system falls within the set range. It is preferred to adjust the speed. The time required for the addition is preferably selected from 0.5 to 6 hours.

  In the production method of the present invention, the reaction temperature of the Grignard reagent and the acid anhydride is 0 ° C. or less. More preferably, it is -40 ° C to -5 ° C. When the reaction temperature exceeds 0 ° C., a Grignard reagent is further reacted with the generated 3'-trifluoromethyl group-substituted aromatic ketone, and the reaction yield of the 3'-trifluoromethyl group-substituted aromatic ketone is lowered. .

  In the production method of the present invention, the reaction time of the Grignard reagent and the acid anhydride is usually 0.5 to 40 hours after mixing all the solutions containing the Grignard reagent solution and the acid anhydride.

  In the production method of the present invention, after completion of the reaction between the Grignard reagent and the acid anhydride, a salt consisting of a 3'-trifluoromethyl group-substituted aromatic ketone and magnesium halide is formed, so this is hydrolyzed. As a result, a 3'-trifluoromethyl group-substituted aromatic ketone is obtained. Preferably, water, acidic water or alkaline water is added to the reaction completed solution to hydrolyze a salt composed of a 3'-trifluoromethyl group-substituted aromatic ketone and magnesium halide. It is preferable to remove the formed magnesium halide into an aqueous phase and then isolate a 3'-trifluoromethyl group-substituted aromatic ketone from the obtained oil phase.

  In the production method of the present invention, the 3 '-trifluoromethyl group-substituted aromatic ketone produced is represented by the following formula.

（但し、ｎは、１〜４の整数である）

(Where n is an integer from 1 to 4)

  In the production method of the present invention, the 3'-trifluoromethyl group-substituted aromatic ketone to be produced is 3'-trifluoromethylacetophenone, 3'-trifluoromethylpropiophenone, 3'-trifluoromethylbutyrophenone, 3 It is' -trifluoromethylvalerophenone, preferably 3'-trifluoromethylacetophenone, 3'-trifluoromethylpropiophenone, 3'-trifluoromethylbutyrophenone.

  Methods of isolating the desired 3'-trifluoromethyl group-substituted aromatic ketone from the reaction solution of the present invention include distillation, crystallization, extraction, column separation with silica, etc., simulated moving bed adsorption separation, etc. It is possible to combine two or more methods. For example, in the distillation method, simple distillation, rectification, vacuum distillation, or atmospheric distillation is preferable, and vacuum distillation is more preferably used.

  The 3'-trifluoromethyl group-substituted aromatic ketone obtained by the production method of the present invention is a compound useful in a wide variety of fields, and therefore, the importance of efficiently and industrially obtaining it is significant.

  Hereinafter, the present invention will be described in more detail by way of examples. In addition, the maker grade of the reagents used here corresponds to all in the first grade level or more.

Example 1
75.0 g of tetrahydrofuran (1.04 mol; made by nacalai tesque), 5.1 g of magnesium powder (0.208 mol; made by Chuo Kogyo Co., Ltd.), 8.5 g of LiCl (0.2 mol; made by nacalai tesque) with a thermometer The mixture was charged into a four-necked flask (200 ml) and stirred while replacing the system with nitrogen. To this was added 0.5 g of a 1 mol / L ethylmagnesium bromide tetrahydrofuran solution (manufactured by Tokyo Chemical Industry Co., Ltd.) to remove water in the system. Subsequently, 0.44 g (0.004 mol; Wako Pure Chemical Industries, Ltd.) of ethyl bromide was added. After stirring for a while, it was confirmed that an exotherm occurred. Next, 45.0 g (0.2 mol; Wako Pure Chemical Industries, Ltd.) of m-bromobenzotrifluoride was gradually added dropwise while maintaining the reaction solution temperature at 30 to 40 ° C. After completion of the addition, the mixture was aged while stirring at 35 ° C. for 3 hours, and 13.5 g (0.3 times by weight / m-bromobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) of toluene was added to obtain a Grignard reagent solution. .

  Next, 19.8 g of acetic anhydride (0.2 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 54.0 g of toluene (1.2 times by weight / m-bromobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) are attached with a thermometer. The mixture was poured into a neck flask (200 ml) and stirred in a -15 ° C cooling bath while replacing the system with nitrogen. The Grignard reagent solution was added dropwise to this while controlling the temperature of the reaction solution to -10 ° C to -5 ° C. After dripping the whole Grignard reagent solution, it stirred at room temperature for 2 hours.

  After completion of the stirring, the reaction solution was cooled to room temperature, and 51.3 g of a 12.2% aqueous hydrogen chloride solution was gradually added dropwise in a water bath. After dripping, the hydrolysis was completed by stirring for 1 hour. After hydrolysis, the stirring was stopped, and stationary phase separation gave an oil phase containing 3 '-trifluoromethylacetophenone.

  The obtained oil phase was analyzed by gas chromatography (GC). As a result, the reaction yield of 3'-trifluoromethylacetophenone was 81.3% (based on the starting material m-bromobenzotrifluoride).

Comparative Example 1
The reaction was performed in the same manner as in Example 1 except that LiCl was not added in Example 1. The obtained oil phase was analyzed by gas chromatography. As a result, the reaction yield of 3'-trifluoromethylacetophenone was 31.7% (based on the starting material m-bromobenzotrifluoride).

Comparative Example 2
In Example 1, the reaction was carried out in the same manner as in Example 1 except that the input amount of LiCl was changed to 1.7 g (0.04 mol). As a result of analyzing the obtained oil phase by gas chromatography, the reaction yield of 3'-trifluoromethylacetophenone was 38.1% (based on the starting material m-bromobenzotrifluoride).

Comparative Example 3
A reaction was performed in the same manner as in Example 1 except that the Grignard reagent solution was added dropwise to the toluene mixed solution of acetic anhydride while controlling the reaction solution temperature to 20 to 30 ° C. in Example 1. As a result of analyzing the obtained oil phase by gas chromatography, the reaction yield of 3'-trifluoromethylacetophenone was 59.3% (based on the starting material m-bromobenzotrifluoride).

Example 2
The oil phase obtained in Example 1 was subjected to vacuum distillation (pressure reduction degree 0.4 to 1.3 kPa, distillation temperature 90 to 100 ° C.), and as a result, the total yield 70.7% (based on the raw material m-bromobenzotrifluoride) ) Gave 3′-trifluoromethylacetophenone having a GC purity of 99.7%.

  The process for producing a 3'-trifluoromethyl group-substituted aromatic ketone of the present invention produces a Grignard reagent as an intermediate in the presence of lithium chloride without using expensive raw materials, and this Grignard reagent with an acid anhydride Can be produced at a reaction temperature of 0 ° C. or less to produce a 3′-trifluoromethyl group-substituted aromatic ketone. The method for producing the 3 '-trifluoromethyl group-substituted aromatic ketone of the present invention is an industrially excellent production method.

  The 3'-trifluoromethyl group-substituted aromatic ketone produced by the method for producing a 3'-trifluoromethyl group-substituted aromatic ketone of the present invention is a fine chemical, a medical and agricultural chemical raw material, a resin / plastics raw material, an electronic information material, an optical information material It can be used as a material or the like.

Claims (4)

A 3-halogen-substituted benzotrifluoride compound represented by the following general formula

(Where X is Cl or Br)
It is reacted with magnesium metal in the presence of 1.0 or more moles of lithium chloride to convert it to a Grignard reagent, and the Grignard reagent is reacted with an acid anhydride at a reaction temperature of 0 ° C. or less and then subjected to hydrolysis treatment A method for producing a 3'-trifluoromethyl group-substituted aromatic ketone, which produces a 3'-trifluoromethyl group-substituted aromatic ketone represented by the following general formula.

(Where n is an integer from 1 to 4)   The method for producing a 3'-trifluoromethyl group-substituted aromatic ketone according to claim 1, wherein the acid anhydride is acetic anhydride, propionic anhydride or butyric anhydride.   The method according to claim 1 or 2, wherein the 3'-trifluoromethyl group-substituted aromatic ketone is 3'-trifluoromethylacetophenone, 3'-trifluoromethylpropiophenone, or 3'-trifluoromethylbutyrophenone. Process for producing 2'-trifluoromethyl group substituted aromatic ketone.   The 3'-trifluoromethyl group-substituted aroma according to any one of claims 1 to 3, wherein the amount of the lithium chloride is 1.0 to 2.0 mol times the amount of the 3-halogen-substituted benzotrifluoride compound. Of making a group ketone.