阅读说明：本技术 环烷基(三氟甲基)苯的制造方法 (Process for producing cycloalkyl (trifluoromethyl) benzene ) 是由 中谷仁郎 于 2018-07-06 设计创作，主要内容包括：本发明提供没有复杂的工序,工序数少的生产效率高的工业上优异的环烷基(三氟甲基)苯的制造方法。使卤素取代三氟甲基苯与镁金属反应,转化成格氏试剂,使该格氏试剂在铁盐或钴盐的存在下,与环烷基卤化物在反应温度60～80℃下进行交叉偶联,从而制造环烷基(三氟甲基)苯。(The present invention provides a method for producing an industrially excellent cycloalkyl (trifluoromethyl) benzene, which does not require a complicated step, has a small number of steps, and has high production efficiency. Reacting halogen-substituted trifluoromethyl benzene with magnesium metal to convert the halogen-substituted trifluoromethyl benzene into a Grignard reagent, and performing cross coupling on the Grignard reagent and a cycloalkyl halide at the reaction temperature of 60-80 ℃ in the presence of an iron salt or a cobalt salt to prepare cycloalkyl (trifluoromethyl) benzene.)

1. A process for producing cycloalkyl (trifluoromethyl) benzene, which comprises reacting a halogen-substituted trifluoromethyl benzene represented by the following general formula (1) with magnesium metal to convert the benzene into a Grignard reagent, and subjecting the Grignard reagent to cross-coupling with a cycloalkyl halide in the presence of an iron salt or a cobalt salt at a reaction temperature of 60 to 80 ℃ to produce cycloalkyl (trifluoromethyl) benzene represented by the following general formula (2),

wherein X is Cl or Br, and n is 1 or 2;

wherein R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and n is 1 or 2.

2. The method for producing a cycloalkyl (trifluoromethyl) benzene according to claim 1, wherein the iron salt is at least one selected from the group consisting of ferrous chloride, ferric acetate (II, III), and ferric acetylacetonate (II, III).

3. The method for producing a cycloalkyl (trifluoromethyl) benzene according to claim 1, wherein the cobalt salt is at least one selected from the group consisting of cobalt (II, III) chloride and cobalt (II, III) acetylacetonate.

4. The process for producing a cycloalkyl (trifluoromethyl) benzene according to claim 1, 2 or 3, wherein N-methylpyrrolidone is allowed to coexist in the cross-coupling reaction system in which the Grignard reagent is allowed to react with a cycloalkyl halide in the presence of an iron salt or a cobalt salt.

5. The method for producing a cycloalkyl (trifluoromethyl) benzene according to any one of claims 1 to 4, wherein the iron salt or cobalt salt is treated with a reducing agent, and then the Grignard reagent and a cycloalkyl halide are cross-coupled.

6. The method for producing a cycloalkyl (trifluoromethyl) benzene according to any one of claims 1 to 5, wherein the reducing agent is a Grignard reagent having 1 to 4 carbon atoms.

Technical Field

The present invention relates to a method for producing a cycloalkyl (trifluoromethyl) benzene, and more particularly, to a method for producing an industrially excellent cycloalkyl (trifluoromethyl) benzene.

Background

Cycloalkyl (trifluoromethyl) benzenes are compounds useful in fine chemicals, raw materials for medicines and agricultural chemicals, raw materials for resins and plastics, electronic information materials, optical materials, and the like.

As a method for producing a cycloalkyl (trifluoromethyl) benzene, patent document 1 discloses lithiating 1-bromo-2- (trifluoromethyl) benzene with butyl lithium to react cyclopentanone with the lithium to produce 1- (2- (trifluoromethyl) phenyl) cyclopentanol. It is further dehydrated and hydrogenated to obtain 1-cyclopentyl-2- (trifluoromethyl) benzene.

In patent document 2, 1-bromo-2- (trifluoromethyl) benzene is grignard-exchanged with isopropyl magnesium bromide, and then reacted with cyclohexanone to produce 1- (2- (trifluoromethyl) phenyl) cyclohexanol. It is further dehydrated and hydrogenated to obtain 1-cyclohexyl-2- (trifluoromethyl) benzene.

Non-patent document 1 discloses a method of performing a cross-coupling reaction of 4- (trifluoromethyl) phenylmagnesium bromide and cyclohexyl bromide at a low temperature of-78 to 0 ℃ using a catalyst in which N, N' -tetramethylethylenediamine is coordinated with ferric chloride.

Non-patent documents 2, 3, and 4 disclose a method of using a catalyst in which a specific ligand is coordinated to iron chloride in a cross-coupling reaction of a phenylmagnesium halide and a cycloalkyl halide.

However, the method described in patent document 1 requires a dehydration reaction, a hydrogenation reaction, and a multi-stage reaction step after the lithiation reaction performed at an extremely low temperature of-78 ℃.

Patent document 2 also requires a dehydration reaction, a hydrogenation reaction, and a multi-stage reaction step after the grignard exchange reaction, which is not high in productivity, because a dilute isopropyl magnesium bromide is used.

These methods involve a reaction step with low productivity in a very low temperature and dilute solution, and thus involve complicated multi-stage reaction steps, and thus the obtained cycloalkyl (trifluoromethyl) benzene is expensive.

The method described in non-patent document 1 discloses that 1-cyclohexyl-4- (trifluoromethyl) benzene is obtained at a yield of 67% by a cross-coupling reaction of 4- (trifluoromethyl) phenylmagnesium bromide and cyclohexyl bromide at a low temperature of-78 to 0 ℃ using a catalyst obtained by complexing expensive N, N' -tetramethylethylenediamine with ferric chloride, but the yield is as low as 44% by using 1.5 equivalents of excess 4- (trifluoromethyl) phenylmagnesium bromide, if the yield is based on 4- (trifluoromethyl) phenylmagnesium bromide.

The ligands disclosed in non-patent documents 2, 3 and 4 are expensive or unavailable, and have problems in industrial use, and it is not clear whether they can be applied to cycloalkyl (trifluoromethyl) benzene of the present invention.

There is a problem in the industrial use of these methods for producing cycloalkyl (trifluoromethyl) benzene, and an inexpensive method for producing cycloalkyl (trifluoromethyl) benzene is desired.

Disclosure of Invention

Problems to be solved by the invention

The purpose of the present invention is to provide an industrially excellent process for producing a cycloalkyl (trifluoromethyl) benzene, which does not require a complicated step, has a small number of steps, and is highly efficient.

Means for solving the problems

The present invention is a process for producing a cycloalkyl (trifluoromethyl) benzene, which comprises reacting a halogen-substituted trifluoromethyl benzene represented by the following general formula (1) with magnesium metal to convert the resulting product into a Grignard reagent, and subjecting the Grignard reagent and a cycloalkyl halide to cross-coupling in the presence of an iron salt or a cobalt salt at a reaction temperature of 60 to 80 ℃ to produce a cycloalkyl (trifluoromethyl) benzene represented by the following general formula (2).

(wherein, X is Cl or Br, and n is 1 or 2.)

(wherein, R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and n is 1 or 2.)

ADVANTAGEOUS EFFECTS OF INVENTION

The process for producing a cycloalkyl (trifluoromethyl) benzene of the present invention uses an inexpensive halogen-substituted trifluoromethylbenzene as a starting substrate. In addition, the present invention is an industrially excellent production method in which a grignard reagent is produced as an intermediate without using an expensive raw material, and the grignard reagent is subjected to a cross-coupling reaction with a cycloalkyl halide in the presence of an iron salt or a cobalt salt, thereby efficiently producing a cycloalkyl (trifluoromethyl) benzene.

The cycloalkyl (trifluoromethyl) benzene produced by the method for producing a cycloalkyl (trifluoromethyl) benzene of the present invention can be used as a material for fine chemicals, medicines and agricultural chemicals, a material for resins and plastics, an electronic information material, an optical material, and the like.

Detailed Description

The details of the present invention are described below.

The process for producing a cycloalkyl (trifluoromethyl) benzene of the present invention uses a halogen-substituted trifluoromethyl benzene represented by the following general formula (1) as a starting substrate.

(wherein, X is Cl or Br, and n is 1 or 2)

Specific examples of the halogen-substituted trifluoromethylbenzene include o-chlorotrifluoromethylbenzene, o-bromotrifluorotoluene, m-chlorotrifluoromethylbenzene, m-bromotrifluorotoluene, p-chlorotrifluoromethylbenzene, p-bromotrifluorotoluene, 1-chloro-3, 5-bis (trifluoromethyl) benzene, and 1-bromo-3, 5-bis (trifluoromethyl) benzene.

In the present invention, the Cl or Br atom of the halogen-substituted trifluoromethylbenzene is reacted with magnesium metal to convert into a Grignard reagent. The conversion reaction into the grignard reagent may utilize a known conversion reaction.

The magnesium metal includes powdered or chip-like magnesium metal, but in terms of operation, it is preferable to use chip-like magnesium metal. The amount of magnesium metal used is preferably 0.8 to 3 moles per 1 mole of the halogen-substituted trifluoromethylbenzene as the raw material.

In the present invention, in order to remove the surface oxide film of magnesium metal and improve the reactivity, iodine, bromine, or an inexpensive compound containing these is preferably added to a solvent containing magnesium metal. Preferable examples of such a compound include methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like.

In the present invention, the reaction for converting into the grignard reagent is carried out in a dehydrated system. Therefore, the reaction may be carried out using a solvent dehydrated in advance, or an inexpensive grignard reagent may be added to the solvent before the reaction to remove water contained in the solvent.

The solvent used for producing the grignard reagent is a solvent capable of efficiently carrying out the reaction. The solvent used for producing the grignard reagent is preferably an ether solvent that easily generates the grignard reagent. Specific examples of the solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and 1, 3-bis (methyl pyrrolidone)

Alkane, 1, 4-di

Alkanes, cyclopropylmethyl ether, methyl-t-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, preferred are diethyl ether, diisopropyl ether, tetrahydrofuran and 1, 3-bisAlkane, 1, 4-di

Alkyl, cyclopropyl methyl ether, methyl-tert-butyl ether.

The amount of the solvent to be used is preferably determined in accordance with the solubility of the halogen-substituted trifluoromethylbenzene 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 moles based on 1 mole of the halogen-substituted trifluoromethylbenzene. If the amount is less than 1 mole, the yield of the Grignard reagent may be low, and if it exceeds 100 moles, the productivity may be deteriorated, which may result in an uneconomical process.

In the production of the grignard reagent of the present invention, when the halogen-substituted trifluoromethylbenzene represented by the above general formula (1) is reacted with magnesium metal to convert into the grignard reagent, LiCl (lithium chloride) is preferably allowed to coexist. The reason is that by allowing LiCl to coexist, the generation of the grignard reagent rapidly occurs, after which the cross-coupling reaction with the cycloalkyl halide occurs in high yield.

In the conversion into the grignard reagent, the amount of LiCl used is preferably 0.01 to 3mol based on 1mol of the halogen-substituted trifluoromethylbenzene. More preferably 0.05 to 1 mol. If the amount of LiCl is 0.01 to 3 times by mole with respect to the halogen-substituted trifluoromethylbenzene, the formation of the Grignard reagent occurs more rapidly, and LiCl is completely dissolved in the reaction system.

Specific examples of the cycloalkyl halide reacted with the grignard reagent in the production method of the present invention include cyclopropyl chloride, cyclopropyl bromide, cyclobutyl chloride, cyclobutyl bromide, cyclopentyl chloride, cyclopentyl bromide, cyclohexyl chloride, cyclohexyl bromide, cycloheptyl chloride and cycloheptyl bromide. Preferred are cyclopropyl bromide, cyclobutyl bromide, cyclopentyl bromide, cyclohexyl bromide and cycloheptyl bromide.

The amount of the cycloalkyl halide to be used is preferably 0.5 to 10 mol, more preferably 1 to 2mol, based on 1mol of the halogen-substituted trifluoromethylbenzene. If the amount is less than 0.5 mol, the compound is produced by self-coupling (homocoupling) of Grignard reagents to each other, and the yield is lowered. If the amount is more than 10 moles, unreacted cycloalkyl halide may remain, resulting in poor productivity, and the load for separating unreacted cycloalkyl halide from cycloalkyl (trifluoromethyl) benzene may increase.

In the present invention, a cycloalkyl halide is reacted with a grignard reagent in the presence of an iron salt or a cobalt salt. Preferred iron salts are ferrous chloride, ferric acetate (including ferric (ii) and ferric (iii) acetate), ferric acetylacetonate (including ferric (ii) and ferric (iii) acetylacetonate), and preferred cobalt salts are cobalt chloride (including cobalt (ii) and cobalt (iii) chloride), cobalt acetylacetonate (including cobalt (ii) and cobalt (iii) acetylacetonate).

The amount of the iron salt or cobalt salt to be used is preferably 0.005 to 1.0 mol, more preferably 0.01 to 0.5 mol, based on 1mol of the halogen-substituted trifluoromethylbenzene Grignard reagent.

In the present invention, it is preferable to use a grignard reagent and a cycloalkyl halide by reducing an iron salt or a cobalt salt before the reaction. Specifically, the iron salt or cobalt salt can be reduced by dissolving the iron salt or cobalt salt in the reaction system and then adding a reducing agent. Specific examples of the reducing agent include lithium aluminum hydride, sodium borohydride, sulfite, hydrazine, diisobutylaluminum hydride, oxalic acid, formic acid, and a Grignard reagent having 1 to 4 carbon atoms, and among them, a Grignard reagent having 1 to 4 carbon atoms is preferable. Examples of the Grignard reagent having 1 to 4 carbon atoms include methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride, tert-butyl magnesium chloride and tert-butyl magnesium bromide.

The timing of the reduction treatment of the iron salt or cobalt salt is not particularly limited as long as it is before the reaction of the cycloalkyl halide with the grignard reagent. For example, the solution containing the cycloalkyl halide may be reduced by adding a reducing agent after adding an iron salt or cobalt salt, or the solution containing the iron salt or cobalt salt may be reduced by adding a reducing agent before adding the solution into the solution containing the cycloalkyl halide.

The amount of the reducing agent is 0.5 to 30 molar times, preferably 1.0 to 15 molar times, the molar number of the iron salt or the cobalt salt.

The temperature for reducing the iron salt or cobalt salt is preferably 20 to 80 ℃, and more preferably 40 to 60 ℃.

In the present invention, it is preferable to add N-methylpyrrolidone in advance together with an iron salt or a cobalt salt in the cross-coupling reaction system in which the Grignard reagent is reacted with the cycloalkyl halide. The reason is that N-methylpyrrolidone coordinates with an iron salt or a cobalt salt to become a catalyst species suitable for the reaction of the grignard reagent and the cycloalkyl halide, and the yield of cycloalkyl (trifluoromethyl) benzene is improved.

The amount of N-methylpyrrolidone added is 0.5 to 20 molar times the number of moles of iron salt or cobalt salt, but N-methylpyrrolidone may be used as a solvent for the reaction between the Grignard reagent and the cycloalkyl halide.

In the present invention, a solvent may be used for the cross-coupling reaction of the grignard reagent with the cycloalkyl halide. The solvent is preferably a solvent which does not inhibit the reaction and enables the reaction to proceed efficiently. Specific examples of the solvent include diethyl ether, diisopropyl ether, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, cyclopropyl methyl ether, methyl-tert-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, benzene, toluene, and xylene. Among them, preferred are N-methylpyrrolidone, tetrahydrofuran, cyclopropylmethyl ether, benzene, toluene, xylene and mesitylene. More preferred is N-methylpyrrolidone.

The amount of the solvent used in the cross-coupling reaction is preferably 0.05 to 50 times the weight of the halogen-substituted trifluoromethylbenzene Grignard reagent. If the amount of the solvent used is less than 0.05 times by weight, the reaction heat is difficult to remove, and the reaction may run away. If the amount is more than 50 times by weight, the productivity may be poor.

The reaction method of the grignard reagent and the cycloalkyl halide may be a method in which a solution containing the cycloalkyl halide is put into a grignard reagent solution, or a method in which a grignard reagent solution is put into a solution containing the cycloalkyl halide. Preferably, the iron or cobalt salt is pre-added to the solution comprising the cycloalkyl halide. In order to prevent a rapid exothermic reaction or runaway reaction, it is preferable to adjust the feeding rate while controlling the temperature in the reaction system so that the temperature becomes a set range, for example, by feeding the solution to be fed continuously or intermittently over time. The time required for charging is preferably 0.5 to 6 hours.

In the production method of the present invention, the cross-coupling reaction of the grignard reagent and the cycloalkyl halide is carried out at a reaction temperature of 60 to 80 ℃. If the reaction temperature is lower than 60 ℃, the self-coupling reaction of Grignard reagents with each other as a side reaction proceeds preferentially, and bis (trifluoromethyl) biphenyl is produced in a large amount. Further, if it exceeds 80 ℃, the Grignard reagent is thermally decomposed before the reaction to produce benzotrifluoride as a by-product. The reaction temperature is preferably 65-75 ℃.

In the production method of the present invention, the reaction time of the cross-coupling reaction of the grignard reagent and the cycloalkyl halide is usually 0.5 to 40 hours, preferably 1.0 to 5 hours at 60 to 80 ℃ after mixing the grignard reagent solution and the cycloalkyl halide-containing solution in the total amount.

In the production method of the present invention, it is preferable that after the completion of the reaction of the cross-coupling reaction of the grignard reagent and the cycloalkyl halide, water, acidic water or alkaline water is added to inactivate the reaction solution and remove the generated magnesium halide to an aqueous phase. Further, the cycloalkyl (trifluoromethyl) benzene can be isolated from the resulting oil phase.

In the production method of the present invention, the produced cycloalkyl (trifluoromethyl) benzene is represented by the following general formula (2).

(wherein, R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and n is 1 or 2)

Examples of the cycloalkyl (trifluoromethyl) benzene produced in the production process of the present invention include 1-cyclopentyl-2-trifluoromethylbenzene, 1-cyclohexyl-2-trifluoromethylbenzene, 1-cyclopentyl-4-trifluoromethylbenzene, 1-cyclohexyl-4-trifluoromethylbenzene, 1-cyclopentyl-3-trifluoromethylbenzene, and 1-cyclohexyl-3-trifluoromethylbenzene. Preferred are 1-cyclopentyl-2-trifluoromethylbenzene and 1-cyclohexyl-2-trifluoromethylbenzene.

Examples of the method for isolating the target cycloalkyl (trifluoromethyl) benzene from the reaction solution of the present invention include distillation, crystallization, extraction, column separation using silica or the like, simulated moving bed adsorption separation, and the like, and various methods can be combined. For example, as the distillation method, simple distillation, rectification, distillation under reduced pressure, and distillation under atmospheric pressure are preferable, and distillation under reduced pressure is more preferable.

The cycloalkyl (trifluoromethyl) benzene obtained by the production method of the present invention is a compound useful in various fields, and therefore, it is of great significance to industrially obtain the compound with high efficiency.