JP5060098B2 - Method for producing biphenyl derivative - Google Patents

Description

  The present invention relates to a method for producing a biphenyl derivative, and more particularly, to an industrially superior method for producing a biphenyl derivative.

  Biphenyl derivatives are compounds that are widely used in the fields of organic chemistry and polymer chemistry, and are useful in a wide range of industrial applications, such as fine chemicals, raw materials for pharmaceuticals and agricultural chemicals, raw materials for resins and plastics, electronic information materials, and optical materials. .

  As a method for producing a biphenyl derivative, it is known that an aromatic halide is used as a starting substrate. Patent Document 1 proposes a method of reacting an aromatic chlorinated Grignard reagent with an aromatic bromide in the presence of a nickel catalyst. On the other hand, Non-Patent Documents 1 and 2 show that after an aromatic iodide or aromatic bromide is reacted with magnesium and converted to a Grignard reagent, an iron (III) chloride catalyst is used, and in the presence of an oxidizing agent, Grignard reagents Proposes a manufacturing method for coupling the.

However, in the method described in Patent Document 1, when the substrate to be reacted with the Grignard reagent is an aromatic chlorinated product, the yield of the biphenyl derivative is low and it cannot be applied industrially. In addition, although the production methods described in Non-Patent Documents 1 and 2 have high reactivity as a starting substrate, an expensive aromatic iodide or aromatic bromide is used, so that the produced biphenyl derivative is also expensive. It had become.
JP 63-295520 A (Examples 1, 2, 3, 4) ORGANIC LETTERS Vol.7, No.3 (2005), 491-493 ORGANIC LETTERS Vol.7, No.10 (2005), 1943-1946

  The objective of this invention is providing the manufacturing method of the biphenyl derivative which was industrially excellent in productivity by using the cheaply and easily available raw material.

  The method for producing a biphenyl derivative of the present invention is a method for producing a biphenyl derivative represented by the following general formula (1), wherein a chlorine atom of a benzene derivative represented by the following general formula (2) is reacted with magnesium metal to form a Grignard reagent. The Grignard reagent is converted into a coupling reaction in the presence of a catalyst.

（ただし、Ａは、トリフルオロメチル基を表し、ｎは、１〜４の整数とする。）

(However, A represents a trifluoromethyl group, and n is an integer of 1 to 4.)

（ただし、Ａは、トリフルオロメチル基を表し、ｎは、１〜４の整数とする。）

(However, A represents a trifluoromethyl group, and n is an integer of 1 to 4.)

  Since the method for producing a biphenyl derivative of the present invention uses an inexpensive aromatic chlorinated compound as a starting substrate, a Grignard reagent can be produced as an intermediate at a low cost, and the Grignard reagents are coupled to each other. Thus, the biphenyl derivative can be efficiently produced with high productivity.

Details of the present invention will be described below.
The method for producing a biphenyl derivative of the present invention uses a benzene derivative represented by the following general formula (2) as a starting substrate.

（ただし、Ａは、トリフルオロメチル基を表し、ｎは、１〜４の整数とする。）

(However, A represents a trifluoromethyl group, and n is an integer of 1 to 4.)

  In said Formula (2), n is an integer of 1-4, Preferably it is 1. This is because when n is 1, a cheaper starting substrate can be used, and further, the reaction proceeds more efficiently because there is little steric reaction inhibiting effect due to substituents in this reaction.

Specific examples of starting substrates include o-chlorobenzotrifluoride, m-chlorobenzotrifluoride, p-chlorobenzotrifluoride, di (trifluoromethyl) -chlorobenzene, tri (trifluoromethyl) -chlorobenzene, tetra (tri fluoromethyl) - etc. chlorobenzene as emissions. Among them preferred are, o- chlorobenzoyl trifluoride, m- chloro benzotrifluoride, a p- chlorobenzotrifluoride Rye de.

  In the present invention, the chlorine atom of the benzene derivative of the formula (2) is reacted with magnesium metal to be converted into a Grignard reagent. The conversion reaction to the Grignard reagent is not particularly limited, and a known conversion reaction can be used.

The magnesium metal is not particularly limited, but it is preferable to use a powdery one.
The reaction to convert to a Grignard reagent is performed in a dehydrated system. It is preferable to use a dehydrated solvent or add an inexpensive Grignard reagent to remove water.

  In addition, iodine, bromine, or an inexpensive compound containing these may be added to increase the reactivity by taking a magnesium oxide surface oxide film. Preferred examples of such compounds include methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like.

  In the production method of the present invention, the catalyst used for the coupling reaction between Grignard reagents is preferably Fe, Ag, Cu, Co, Zn, Ni, Pd metal or a compound thereof, and the compound is a chloride of these metals. , Bromide, iodide, fluoride, acetate, acetylacetonate, carbonate, hydroxide, and nitrate are preferably used. Of these, ferrous chloride (II), ferric chloride (III), ferrous bromide, and ferric bromide are preferable.

  The catalyst is preferably used in an amount of 0.01 mol% to 20 mol%, more preferably 0.05 mol% to 10 mol%, relative to 1 mol of the starting substrate. By making the usage-amount of a catalyst into said range, a coupling reaction can be performed efficiently and economically.

  In the production method of the present invention, the coupling reaction is preferably performed in the presence of an oxidizing agent. This is because in the presence of an oxidizing agent, the catalyst reduced by the coupling reaction is easily oxidized and regenerated, so that the turnover number of the catalyst is improved and the reaction yield is improved.

  The oxidizing agent is not particularly limited as long as it can oxidize metals, but from the viewpoint of handling and separation from products, halogenated aliphatic hydrocarbons are preferred, and halogens having 1 to 5 carbon atoms. More preferred are aliphatic hydrocarbons. Specifically, chloromethane, dichloromethane, chloroform, carbon tetrachloride, bromomethane, dibromomethane, tribromomethane, tetrabromomethane, chloroethane, dichloroethane, trichloroethane, tetrachloroethane, tetrachloroethylene, pentachloroethane, hexachloroethane, bromoethane, dibromoethane , Tribromoethane, tetrabromoethane, chloropropane, dichloropropane, trichloropropane, chlorobutane, dichlorobutane, chloropentane, dichloropentane, bromopropane, dibromopropane, tribromopropane, bromochloromethane, bromochloroethane and the like. Of these, chloromethane, dichloromethane, chloroethane, dichloroethane, dichloropropane, bromomethane, dibromomethane, bromoethane, dibromoethane, and dibromopropane are preferable, and dichloropropane is more preferable.

  The amount of the oxidizing agent used is preferably 0.1 mol times to 5 mol times, more preferably 0.2 mol times to 3 mol times based on 1 mol of the starting substrate. If the amount is less than 0.1 mol, the effect of catalyst regeneration by the oxidant is small. If the amount is more than 5 mol, the amount of unreacted oxidant remains, which is inefficient in isolating and purifying the target product. Is.

  As the solvent used in the production method of the present invention, any solvent can be arbitrarily selected as long as the reaction can proceed efficiently. Preferably, an ether solvent that can easily generate a Grignard reagent is preferable. 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, cyclopropylmethyl ether. 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. Of these, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, cyclopropyl methyl ether, and methyl tertiary butyl ether are preferable.

  The solvent may be used in any amount depending on the solubility of the benzene derivative represented by the formula (2), the Grignard reagent, and the product, the slurry concentration, or the properties of the reaction solution. The amount is 0.5 to 100 mole times the benzene derivative represented by the formula (2). If the amount is less than 0.5 mole times, the yield of the Grignard reagent will be low, and if it exceeds 100 mole times, the productivity will be poor and an uneconomic process will occur.

  In the production method of the present invention, the reaction temperature of the coupling reaction is preferably 45 to 100 ° C, more preferably 55 to 70 ° C. If the reaction temperature is lower than 45 ° C, the reaction hardly proceeds. Even if the reaction proceeds, the reaction may stop halfway. If the reaction temperature exceeds 100 ° C, the Grignard reagent will decompose before reacting. This is not preferable.

  In the production method of the present invention, during the coupling reaction, together with the target biphenyl derivative represented by the following general formula (1), a halogenated biphenyl derivative represented by the following general formula (3) is by-produced, A composition comprising a biphenyl derivative is obtained.

（ただし、Ａは、トリフルオロメチル基を表し、ｎは、１〜４の整数とする。）

(However, A represents a trifluoromethyl group, and n is an integer of 1 to 4.)

（ただし、Ａは、トリフルオロメチル基を表し、Ｘは、ハロゲン原子を表し、ｎは、１〜４の整数、ａ及びｂは、整数でありａとｂの合計が１〜８とする。）

(However, A represents a trifluoromethyl group , X represents a halogen atom, n is an integer of 1 to 4, a and b are integers, and the sum of a and b is 1 to 8. )

  In the composition containing the biphenyl derivative obtained by the production method of the present invention, the content of the halogenated biphenyl derivative represented by the formula (3) is preferably 20% by weight or less, and 0.01% by weight to 20% by weight. % Is more preferable. This is because when the halogenated biphenyl derivative exceeds 20% by weight, the quality of the final product is deteriorated when used as a raw material for fine chemicals, raw materials for medicines and agricultural chemicals, resin / plastic raw materials, electronic information materials, optical materials and the like. That is, it is not preferable because quality problems such as a decrease in purity of the final product, coloring, a decrease in strength, and a decrease in optical characteristics occur.

  Therefore, in the production method of the present invention, when the content of the by-produced halogenated biphenyl derivative is large, the halogenated biphenyl derivative is separated and removed from the obtained coupling reaction solution, and the content is reduced as much as possible. Preferably, the desired biphenyl derivative is isolated. Preferred examples of the isolation method include a distillation purification method, a crystallization method, an extraction method, column separation using silica and the like, and a simulated moving bed adsorption separation method, and any of the isolation methods may be used. Is more preferable. Moreover, it can also refine | purify combining several methods among these isolation methods, and can also raise purity.

  In the present invention, since active magnesium or the like may remain in the reaction solution, water or acidic water is added to the reaction solution, and the magnesium salt produced in the reaction is removed to the aqueous phase, and then obtained. A method of isolating the biphenyl derivative from the obtained oil phase is preferred. For example, as the distillation purification method, any of simple distillation, rectification, vacuum distillation, and atmospheric distillation may be used, but vacuum distillation is preferably used. In distillation purification, since the halogenated biphenyl derivative has a higher boiling point than the target biphenyl derivative, distillation such as distilling the biphenyl derivative, leaving the halogenated biphenyl derivative as little as possible and leaving it in the can residue, etc. Operation is required.

  In the production method of the present invention, the content of the halogenated biphenyl derivative in the biphenyl derivative obtained by any of the isolation methods is preferably 0.01 wt% to 20 wt%, more preferably 0.01 wt%. % To 5% by weight. By setting the content of the halogenated biphenyl derivative within the above range, it is possible to maintain the quality, such as purity, coloring, strength, and optical properties, of the final product using the biphenyl derivative as a raw material.

  The biphenyl derivative obtained by the production method of the present invention can be converted into various compounds in various fields, and it is highly significant that it can be obtained industrially at low cost and efficiently.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this.

  The manufacturer grades of the reagents used in the following examples and comparative examples all correspond to the first grade level or more unless otherwise specified.

Example 1
Tetrahydrofuran 143.6 g (1.99 mol; manufactured by nacalai tesque) and magnesium powder 16.1 g (0.664 mol; manufactured by Chuo Kosan Co., Ltd.) were charged into a reactor equipped with a thermometer, and the system was purged with nitrogen. Stir. Tertiary-butylmagnesium chloride 2 g (0.017 mol; manufactured by Tokyo Chemical Industry Co., Ltd.) was added to remove moisture in the system. Next, 10 g of o-chlorobenzotrifluoride (0.0554 mol; manufactured by MITENI) was added, and then 2 g of ethyl bromide (0.018 mol; manufactured by nacalai tesque) was added. After stirring for a while, it was confirmed that exotherm occurred. Next, 90 g (0.499 mol) of o-chlorobenzotrifluoride was added dropwise while maintaining the reaction solution temperature at 35 to 50 ° C. After completion of dropping, the mixture was aged with stirring at 45 ° C. for 3 hours. The yield of Grignard reagent was 91%.

Next, 65 g (0.664 mol; nacalai tesque) of 1,2-dichloroethane was added to a solution obtained by adding 3 g (0.04 mol) of tetrahydrofuran to 2.70 g (0.0166 mol; manufactured by Wako Pure Chemical Industries, Ltd.) of iron (III) chloride. The catalyst-containing solution was prepared. This was dropped into the Grignard reagent solution while maintaining the reaction solution temperature at 45 to 60 ° C. to carry out a coupling reaction. After completion of dropping, the reaction was carried out at 65 ° C. for 3 hours. After completion of the reaction, it is cooled, the reaction solution is developed into water, the oil layer is extracted with diethyl ether (manufactured by nacalai tesque, special grade), and the internal standard substance acetophenone (manufactured by nacalai tesque, special grade) is added thereto. The gas chromatography method (column: manufactured by GL Science Inc .: inert cap 1 length 60 m × diameter 0.25 mm, film thickness 0.40 μm) was analyzed. The yield of 2,2'- di ( trifluoromethyl ) biphenyl based on o-chlorobenzotrifluoride was 69%. Further, by-produced chloro 2,2′- di ( trifluoromethyl ) biphenyl was 11% by weight based on 2,2′- di ( trifluoromethyl ) biphenyl.

Example 2
In Example 1, the reaction was performed in the same manner as in Example 1 except that the catalyst was changed from iron (III) chloride to 5.86 g (0.0166 mol; manufactured by Wako Pure Chemical Industries, Ltd.) of iron (III) acetylacetonate. . The yield of 2,2'- di ( trifluoromethyl ) biphenyl based on o-chlorobenzotrifluoride was 48%. The by-produced chloro 2,2′- di ( trifluoromethyl ) biphenyl was 6.7% by weight relative to di ( 2,2′-trifluoromethyl ) biphenyl.

Example 8
In Example 1, the reaction was performed in the same manner as in Example 1 except that 1,2-dichloroethane was changed to 124.7 g (0.664 mol; manufactured by Wako Pure Chemical Industries, Ltd.) of 1,2-dibromoethane. The yield of 2,2′- di ( trifluoromethyl ) biphenyl based on o-chlorobenzotrifluoride was 38%. Further, by- produced bromodi ( 2,2′-trifluoromethyl ) biphenyl was 29% by weight based on 2,2′- di ( trifluoromethyl ) biphenyl.

Example 4
In Example 1, the reaction was carried out in the same manner as in Example 1, except that 1,2-dichloroethane was changed to 75.0 g (0.664 mol; manufactured by Wako Pure Chemical Industries, Ltd.) of 1,2-dichloropropane. The yield of 2,2'- di ( trifluoromethyl ) biphenyl based on o-chlorobenzotrifluoride was 72%. The by-produced chloro 2,2′- di ( trifluoromethyl ) biphenyl was 8.5% by weight based on 2,2′- di ( trifluoromethyl ) biphenyl.

Example 5
In Example 4, 75.0 g of 1,2-dichloropropane (0.04 mol) was added to a solution obtained by adding 3 g (0.04 mol) of tetrahydrofuran to 2.70 g (0.0166 mol; manufactured by Wako Pure Chemical Industries, Ltd.) of iron (III) chloride. The reaction was carried out in the same manner as in Example 4 except that the Grignard reagent solution was added dropwise to the catalyst-containing solution to which 664 mol (manufactured by Wako Pure Chemical Industries, Ltd.) was added while maintaining the reaction solution temperature at 45-60 ° C. The yield of 2,2'- di ( trifluoromethyl ) biphenyl based on o-chlorobenzotrifluoride was 73%. The by-produced chloro 2,2′- di ( trifluoromethyl ) biphenyl was 1.7% by weight based on 2,2′- di ( trifluoromethyl ) biphenyl.

Example 6
The reaction was carried out in the same manner as in Example 1 except that o-chlorobenzotrifluoride was changed to m-chlorobenzotrifluoride (manufactured by MITENI) in Example 1. The yield of 3,3′- di ( trifluoromethyl ) biphenyl based on m-chlorobenzotrifluoride was 41%. Further, by-produced chloro 3,3′- di ( trifluoromethyl ) biphenyl was 10.5% by weight based on 3,3′- di ( trifluoromethyl ) biphenyl.

Comparative Example 1
Tetrahydrofuran 143.6 g (1.99 mol; manufactured by nacalai tesque) and magnesium powder 16.1 g (0.664 mol; manufactured by Chuo Kosan Co., Ltd.) were charged into a reactor equipped with a thermometer, and the system was purged with nitrogen. Stir. Tertiary-butylmagnesium chloride 2 g (0.017 mol; manufactured by Tokyo Chemical Industry Co., Ltd.) was added to remove moisture in the system. Next, 10 g of o-chlorobenzotrifluoride (0.0554 mol; manufactured by MITENI) was added, and then 2 g of ethyl bromide (0.018 mol; manufactured by nacalai tesque) was added. After stirring for a while, it was confirmed that exotherm occurred. Next, 90 g (0.499 mol) of o-chlorobenzotrifluoride was added dropwise while maintaining the reaction solution temperature at 35 to 50 ° C. After completion of dropping, the mixture was aged with stirring at 45 ° C. for 3 hours. The yield of Grignard reagent was 91.0%.

Next, a solution prepared by dissolving 3.59 g (0.028 mol; manufactured by nacalai tesque) of anhydrous nickel chloride in 30 g of tetrahydrofuran was slowly added to the Grignard reagent solution while maintaining the liquid temperature at 40 ° C. Next, 100 g of o-chlorobenzotrifluoride was added dropwise while maintaining the reaction temperature at 60 ° C. After completion of the reaction, analysis was performed by gas chromatography in the same manner as in Example 1. The yield of 2,2'- di ( trifluoromethyl ) biphenyl with respect to o-chlorobenzotrifluoride was 2%. Further, no by-product of chloro 2,2'- di ( trifluoromethyl ) biphenyl was observed.

Example 7
100 g of the reaction solution obtained in Example 1 was added to 100 g of 3% aqueous hydrochloric acid solution in a 300 ml separatory funnel, mixed well at room temperature for 30 minutes, and allowed to stand for 30 minutes. After standing, liquid separation was performed to obtain 78.3 g of an oil phase. Then, this oil phase was simply distilled under reduced pressure. After the initial distillation cut, 17.3 g of a distillate at 100 to 130 ° C. was obtained under a vacuum degree of 1.33 kPa. The concentration of 2,2'- di ( trifluoromethyl ) biphenyl in the obtained distillate was 95.6% by weight, and the concentration of chloro 2,2'- di ( trifluoromethyl ) biphenyl was 3.5% by weight. %Met.

Claims (7)

In the method for producing a biphenyl derivative represented by the following general formula (1), the chlorine atom of the benzene derivative represented by the following general formula (2) is reacted with magnesium metal to convert it into a Grignard reagent, and the Grignard reagents are present in a catalyst. A method for producing a biphenyl derivative which undergoes a coupling reaction below.

(However, A represents a trifluoromethyl group, and n is an integer of 1 to 4.)

(However, A represents a trifluoromethyl group, and n is an integer of 1 to 4.)   The method for producing a biphenyl derivative according to claim 1, wherein the number n of the substituents A is 1 in the formula (2).   The method for producing a biphenyl derivative according to claim 1 or 2, wherein the catalyst is at least one metal selected from Fe, Ag, Cu, Co, Zn, Ni, and Pd or a compound thereof.   The method for producing a biphenyl derivative according to claim 1, wherein the coupling reaction is performed in the presence of an oxidizing agent.   The method for producing a biphenyl derivative according to claim 4, wherein the oxidizing agent is a halogenated aliphatic hydrocarbon.   The method for producing a biphenyl derivative according to any one of claims 1 to 5, wherein a reaction temperature of the coupling reaction is 45 to 100 ° C. The method for producing a biphenyl derivative according to claim 5 , wherein the biphenyl derivative is purified by distillation, and the content of the halogenated biphenyl derivative represented by the following general formula (3) is 0.01 wt% to 20 wt%.

(However, A represents a trifluoromethyl group , X represents a halogen atom, n is an integer of 1 to 4, a and b are integers, and the sum of a and b is 1 to 8. )