JP4489532B2 - 3-Formyl-5-trifluoromethylbenzonitrile derivative and process for producing the same - Google Patents

Description

  The present invention provides a novel 3-formyl-5-trifluoromethylbenzonitrile derivative useful as an intermediate or solvent for pharmaceuticals and agricultural chemicals. The present invention also relates to a novel process for producing 3-formyl-5-trifluoromethylbenzonitrile derivatives.

  A 3-formyl-5-trifluoromethylbenzonitrile derivative is, for example, a compound expected as a therapeutic or prophylactic agent for arteriosclerosis or hyperlipidemia (Japanese Patent Laid-Open No. 2003-221376), or an inhibitor of reverse transcriptase. Important in producing promising compounds (WO 02/070470, JP 2003-510252) and promising compounds as metabotropic glutamate receptor antagonists (WO 02/068417) Intermediate.

  As a technique related to the present invention, a method for producing 3-hydroxymethyl-5-trifluoromethylbenzonitrile and 3-formyl-5-trifluoromethylbenzonitrile is disclosed in Patent Document 1 (Scheme 1).

  Regarding 1-bromo-3-formyl-5-trifluoromethylbenzene, it is disclosed in Patent Document 2 that it can be produced by the oxidation reaction of the following scheme 2.

JP 2003-221376 A International Publication No. 02/096849

  An object of the present invention is to provide a method for producing a 3-formyl-5-trifluoromethylbenzonitrile derivative suitable for production on a new industrial scale.

 3-Formyl-5-trifluoromethylbenzonitrile derivatives have three different functional groups on the aromatic ring, but the production of such aromatic rings having three different functional groups generally requires a multi-step process. For this reason, the synthesis method is often complicated, and as a result, problems such as deterioration of the overall yield and generation of by-products that are difficult to separate are likely to occur.

The method of Patent Document 1 uses 3-nitro-5-trifluoromethylbenzoic acid as a starting material, but this is difficult to obtain and expensive, and requires many steps even if synthesized. Furthermore, in order to obtain the target product, multiple steps are required, an expensive borane-tetrahydrofuran complex that is difficult to handle during the process is used, an expensive palladium catalyst is used over two steps, and further in the substrate This process is difficult to employ industrially because a large amount of CuBr ₂ is required in the step of introducing bromine (Br) into the substrate.

 On the other hand, 1-bromo-3-formyl-5-trifluoromethylbenzene can be assumed as a suitable intermediate for producing the desired 3-formyl-5-trifluoromethylbenzonitrile derivative. Conventionally known production methods according to Patent Document 2 use ozone that is difficult and dangerous to handle, and it is difficult to employ this production method industrially.

In producing a series of 3-formyl-5-trifluoromethylbenzonitrile derivatives targeted in the present invention, the bromination step is considered to be the most difficult. In general, the bromination reaction is poor in regioselectivity, and it is rare that a bromine atom can be efficiently introduced into a target site, and an isomer in which bromine is introduced into a different site or an overreaction product is easily generated. This tendency is particularly strong in the case of aromatics having a hydrogen atom at the benzyl position. For example, when N-bromosuccinimide (NBS) is used as a brominating agent, both the benzyl position and the aromatic ring may be brominated. Further, it is shown in Journal of Organic Chemistry, Vol. 63, pages 6023 to 6026, 1998 (USA) that even when sodium bromate is used, a compound in which both the benzyl position and the aromatic ring are brominated is obtained. Has been. Furthermore, when bromine (Br ₂ ) is used to brominate p-nitrotoluene having a nitro group which is a strong electron-attracting group like the trifluoromethyl group, bromine is introduced at the benzyl position instead of the aromatic ring. -It is shown in Organic Syntheses Collective Volume 2, pages 443-445, 1943 (USA) that nitrobenzyl bromides are obtained.

 In general, when a high concentration of hydrobromic acid is allowed to act on benzonitrile, hydrolysis of the nitrile group occurs to produce benzoic acid or benzamide. For example, US Pat. No. 4,868,333 discloses that 2-nitro-4-trifluoromethylbenzoic acid is obtained when 48% hydrobromic acid is allowed to act on 2-nitro-4-trifluoromethylbenzonitrile. Is disclosed.

  Thus, in general, the bromination method has a low reaction selectivity and is performed at a relatively early stage of organic synthesis, that is, in the state of a simple compound without many substituents, or the patent A special brominating agent such as document 1 must be used.

 As described above, the production of 3-formyl-5-trifluoromethylbenzonitrile derivatives, particularly 3-bromomethyl-5-trifluoromethylbenzonitrile, is quite difficult, and it is difficult to establish an industrial production method that can be implemented in the future. It was desired.

 The present inventors have intensively studied to solve the above problems. As a result, 3-formyl-5-trifluoromethylbenzonitrile derivative can be easily obtained with a small number of steps, starting from industrially inexpensive and easily available 3-dihalogenomethylbenzotrifluoride. The method was found and the present invention was completed.

The production method of the present invention is a method for producing a 3-formyl-5-trifluoromethylbenzonitrile derivative comprising at least the first to fifth steps among the following first to seventh steps.
First step: 3-dihalogenomethylbenzotrifluoride represented by the general formula [1]

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene represented by the general formula [2]

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
Obtaining.
Second step: a step of hydrolyzing the 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene to obtain 1-bromo-3-formyl-5-trifluoromethylbenzene.
Third step: a step of reacting the 1-bromo-3-formyl-5-trifluoromethylbenzene with hydroxylamines or an acid adduct thereof to obtain 3-bromo-5-trifluoromethylbenzaldoxime.
Fourth step: a step of dehydrating the 3-bromo-5-trifluoromethylbenzaldoxime to obtain 3-bromo-5-trifluoromethylbenzonitrile.
Fifth step: 3-bromo-5-trifluoromethylbenzonitrile is reacted with alkylmagnesium halide, magnesium metal, or alkyllithium to produce 3-trifluoromethyl-5-cyanophenylmagnesium halide or 3-trifluoromethyl. Step of converting to -5-cyanophenyllithium, followed by formylation to obtain 3-formyl-5-trifluoromethylbenzonitrile Step 6: Reduction of 3-formyl-5-trifluoromethylbenzonitrile -Obtaining hydroxymethyl-5-trifluoromethylbenzonitrile;
Seventh step: a step of brominating the 3-hydroxymethyl-5-trifluoromethylbenzonitrile to obtain 3-bromomethyl-5-trifluoromethylbenzonitrile.

  When producing a 3-formyl-5-trifluoromethylbenzonitrile derivative by these methods, starting materials can be obtained at low cost, and the reaction proceeds smoothly in each step. In particular, when the reaction route of the present invention was taken, both the first step and the seventh step bromination proceeded with high selectivity, and the surprising result that the target compound was obtained in high yield was obtained. In addition, it was found that each process does not produce impurities that are difficult to separate, so that subsequent purification operations are not burdened and are extremely effective means for producing the target product on an industrial scale. .

  The production method of the present invention is summarized as Scheme 3.

  In the first step, 3-dihalogenomethylbenzotrifluoride is brominated to give 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene. Generally, such benzal halides are used. The dihalogenomethyl group of is subject to hydrolysis at high temperatures and easily decomposes. Therefore, until now, such bromination of benzal halides has been hardly known.

The present inventors have found a method and conditions for carrying out the first step particularly effectively. That is, it is known that the bromination is preferably performed using bromine (Br ₂ ) as a brominating agent. In this case, when chlorine (Cl ₂ ) coexists with bromine (Br ₂ ), particularly strong bromination power. Was found to be expressed. In this case, by carrying out the reaction at a relatively low temperature of 100 ° C. or lower, the decomposition of the dihalogenomethyl group is particularly effectively suppressed, and the target 1-bromo-3-di with surprisingly high yield and high selectivity. It has been found that halogenomethyl-5-trifluoromethylbenzene is obtained.

  In the seventh step, 3-hydroxymethyl-5-trifluoromethylbenzonitrile is brominated to obtain 3-bromomethyl-5-trifluoromethylbenzonitrile. Generally, benzonitrile has a high concentration of odor. When hydrofluoric acid is allowed to act, hydrolysis occurs and benzoic acid and benzamide are produced. However, in the present invention, the reaction conditions for the bromination were intensively studied, the conditions for selectively brominating only the hydroxymethyl group without hydrolyzing benzonitrile were found, and the present invention was completed.

  In the present invention, after the basic skeleton of the organic compound is almost completed, the bromination process is performed twice at a relatively late stage, and only the target site is brominated with high selectivity. It is characterized by obtaining the object in

  Among the 3-formyl-5-trifluoromethylbenzonitrile derivatives, 3-bromomethyl-5-trifluoromethylbenzonitrile is a novel compound, and its production method has not been known so far.

1-Bromo-3-dichloromethyl-5-trifluoromethylbenzene and 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzenes are all novel compounds, and their production methods have hitherto been unknown. In addition, there are few known examples of brominating general dichloromethylbenzene, so-called benzal chloride, using bromine (Br ₂ ).

  Prior to the present invention, the present inventors used 1-bromo-3-formyl-5-trifluorobenzene as a raw material, and passed through a process different from that described above to form 3-formyl-5-trifluoromethylbenzoate. An application for a method for producing nitrile has already been filed (Japanese Patent Application No. 2004-085484).

  The method for producing the 3-formyl-5-trifluoromethylbenzonitrile derivative of the present invention can be obtained from 3-dihalogenomethylbenzotrifluoride, which is easily available as an industrial raw material, in a small number of steps and in a good yield. As an intermediate for agricultural chemicals and as a solvent and detergent, 3-formyl-5-trifluoromethylbenzonitrile derivatives are produced on an industrial scale.

  Hereinafter, the present invention will be described in more detail. 3-Dihalogenomethylbenzotrifluoride represented by the general formula [1] as a starting material of the present invention

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
Specifically, 3-difluoromethylbenzotrifluoride, 3-dichloromethylbenzotrifluoride, 3-dibromomethylbenzotrifluoride, 3-diiodomethylbenzotrifluoride, 3-chlorofluoromethylbenzotrifluoride, 3- Examples include bromofluoromethylbenzotrifluoride, 3-fluoroiodomethylbenzotrifluoride, 3-bromochloromethylbenzotrifluoride, 3-chloroiodomethylbenzotrifluoride, and 3-bromoiodomethylbenzotrifluoride. Among these, 3-dibromomethylbenzotrifluoride obtained by brominating the methyl group of m-trifluoromethyltoluene by an existing method, and 3-trichloromethylbenzal chloride obtained by side chain chlorination of m-xylene. 3-dichloromethylbenzotrifluoride, 3-difluoromethylbenzotrifluoride, and 3-chlorofluoromethylbenzotrifluoride obtained by fluorinating benzene with hydrogen fluoride are preferred as starting materials because of their availability and are economical To 3-dichloromethylbenzotrifluoride are particularly preferred.

  First, the first step of the present invention will be described. In this step, the above-mentioned 3-dihalogenomethylbenzotrifluoride is brominated to give 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene represented by the general formula [2].

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
It is the process of obtaining.

Examples of the brominating agent used in this step include bromine (Br ₂ ), benzyltrimethylammonium tribromide, N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethyl-hydantoin (DBH), bromine Known materials such as sodium acid can be used. Of these, when N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethyl-hydantoin (DBH) is used, a strong acid such as concentrated sulfuric acid or trifluoroacetic acid is usually used. The halogenomethyl group may be decomposed and the yield may be reduced. Accordingly, bromine (Br ₂ ), benzyltrimethylammonium tribromide, and sodium bromate are preferred, and bromine (Br ₂ ) is particularly preferred from the viewpoint of economy and availability.

The amount of bromine (Br ₂ ) used is usually 0.5 to 2 mol, preferably 0.5 to 1 mol, more preferably 0.5 to 0. 1 mol per mol of 3-dihalogenomethylbenzotrifluoride. 75 moles. However, in the case where it is not desired to increase the production of the polybromo compound accompanying complete bromination, 0.5 mol or less of bromine (Br ₂ ) can be used. Bromine (Br ₂ ) can be used in an amount of 2 mol or more, but if used in a large amount, it may promote the decomposition of the dihalogenomethyl group or the bromination of the dihalogenomethyl group corresponding to the undesired benzyl position. It is not preferable.

The present process proceeds even using only bromine (Br _2), when using only bromine (Br _2), decomposes the hydrogen bromide by-produced is reacted with a trifluoromethyl group or Jiharogenomechiru group There is a case. Moreover, sufficient bromination power cannot be obtained with bromine alone, and the reaction may be prolonged, resulting in decomposition of the dihalogenomethyl group and bromination of the dihalogenomethyl group corresponding to the benzyl position. In order to avoid them, the present inventors have found that it is particularly preferable to coexist chlorine (Cl ₂ ) in the system.

When chlorine (Cl ₂ ) coexists, it is preferable to use 1 mol or more per 1 mol of bromine (Br ₂ ), but it is sufficient to use about 1 to 2 mol. About 2 moles. When the amount of chlorine (Cl ₂ ) is less than 1 mol, the conversion of bromine (Br ₂ ) is unfavorable, and when it is used more than necessary, chlorine of 3-dihalogenomethylbenzotrifluoride, a by-product, is not preferable. This is not preferable because it promotes the formation of hydride and reduces the yield of 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene, and also makes it difficult to treat chlorine (Cl ₂ ) in the reaction process. It is not preferable.

In general, chlorine (Cl ₂ ) may be charged all at once, but it is preferable to add them continuously or in appropriate divided portions. It is preferable to keep the amount of bromine (Br ₂ ) in the reaction system always excessive with respect to chlorine (Cl ₂ ), because a by-product of chlorinated products can be suppressed. Therefore, it is generally preferable to gradually add chlorine (Cl ₂ ) as the reaction proceeds. In addition, when the reaction is carried out while purging hydrogen chloride produced as a by-product and keeping the reaction pressure constant, a reflux device is installed at the outlet of the reactor, and chlorine (Cl ₂ ) and bromine chloride are refluxed to the reactor. Loss of chlorine (Cl ₂ ) and bromine chloride (BrCl) can be reduced. In the addition of chlorine (Cl ₂ ), an apparatus for promoting gas-liquid contact, for example, a stirrer, a blowing pipe, a porous dispersion pipe (sparger), or the like can be used as appropriate.

 This process proceeds even in the absence of a catalyst, but in the absence of a catalyst, the reaction will be prolonged, resulting in decomposition of the dihalogenomethyl group and bromination of the dihalogenomethyl group corresponding to the benzyl position. There is. We have found that it is preferable to use a catalyst to avoid them.

 As the catalyst used, known catalysts such as a catalyst containing iron, a catalyst containing antimony, and a catalyst containing aluminum known as Lewis acid can be used, but a catalyst containing iron is used from the viewpoint of economy and disposal. Is preferred. As the catalyst containing iron, an iron halide can be preferably used. The catalyst only needs to be a halide in the reaction state, and it may be metallic iron or an alloy or compound containing iron at the time of charging, but usually ferric chloride, ferric bromide, etc., which are easily available. It is particularly preferred to use it. The addition amount of the catalyst is 0.1 to 100 mol, preferably 1 to 50 mol, more preferably 5 to 30 mol as iron with respect to 100 mol of 3-dihalogenomethylbenzotrifluoride. When the amount of the catalyst is less than 0.1 mol, the reaction rate is slow, and when it is more than 100 mol, there is no problem with the progress of the reaction, but there is no merit in terms of reaction rate and yield, and the operation becomes complicated. Therefore, it is not preferable.

 This step may be performed using an inert solvent as a solvent, but if used, the yield per volume is reduced, which is not preferable. In the case where a solvent is used, chlorinated solvents and the like can be mentioned. Examples include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane, pentachloroethane, trichloroethylene, tetrachloroethylene, and the like. These solvents may be used alone or in combination of two or more.

 This process is normally performed at about 25-100 degreeC, 30-90 degreeC is preferable and 40-80 degreeC is more preferable. When the reaction temperature is lower than room temperature, the reaction is slow, and when the reaction temperature is higher than 100 ° C, side reactions such as hydrolysis of the dihalogenomethyl group or bromination of the dihalogenomethyl group corresponding to the benzyl position occur. Is not preferred because it may decrease. The pressure of the reactor is 0.1 to 10 MPa, and preferably 0.3 to 2 MPa.

 This step can be performed using a metal container such as stainless steel, hastelloy, or monel.

This embodiment may be any embodiment. For example, a predetermined amount of 3-dihalogenomethylbenzotrifluoride, bromine (Br ₂ ), iron halide, and an arbitrary amount, for example, a half amount of chlorine (Cl ₂ required for the completion of the reaction) are previously charged in the reactor. ) And the temperature of the reaction solution is raised to a predetermined temperature while stirring, and then the remaining chlorine (Cl ₂ ) gas is blown into the reaction solution in an appropriate number as the reaction proceeds. Hydrogen chloride produced by the reaction is sequentially purged to keep the reaction pressure constant. The reaction is continued in this way, and the reaction is stopped when the composition of 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene reaches a predetermined value. After completion of the reaction, 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene can be obtained by ordinary means such as filtration, extraction, distillation and the like. If necessary, it can be purified by distillation or column chromatography.

 Next, the second step of the present invention will be described. This step is for 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene represented by the above general formula [2].

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
Is hydrolyzed to give 1-bromo-3-formyl-5-trifluoromethylbenzene.

In this step, 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene is converted into general formula [3]
M _n L _m [3]
Wherein M is a transition element selected from iron, nickel, copper, chromium, tantalum and zinc, preferably from iron, copper and zinc, particularly preferably selected from iron and zinc, and L is F , Cl, Br, I, OH, SO ₄ , PO ₄ or NO ₃ , preferably Cl, Br, OH, SO ₄ , PO ₄ or NO ₃ , and n and m depend on the oxidation number of the transition element It is preferably carried out by contacting with water in the presence of one or more catalysts represented by the formula: For example, ferric chloride and ferric bromide are preferably used. The amount of the catalyst is preferably 0.001 mol to 0.05 mol, and more preferably 0.005 mol to 0.03 mol, per mol of 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene. When these catalysts are used as an aqueous solution having a concentration of about 0.1 to 30% by weight, preferably about 0.3 to 10% by weight, the reaction tends to proceed easily.

  The amount of water used in this step is preferably 1.0 mol to 2.0 mol, and 1.0 mol to 1.6 mol per mol of 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene. Further preferred. Although there is no restriction | limiting in particular in the reaction temperature of this process, Preferably it is 0-220 degreeC, More preferably, it is 90-160 degreeC. If it is less than 90 ° C., the reaction is slow. On the other hand, when the temperature exceeds 160 ° C., by-products are likely to be generated, and excessive heating is inferior in energy efficiency and is not preferable from the viewpoint of economy. After completion of the reaction, 1-bromo-3-formyl-5-trifluoromethylbenzene can be obtained by ordinary means such as filtration, extraction, distillation, recrystallization and the like. If necessary, it can be purified by distillation, column chromatography, recrystallization or the like.

Next, the third step of the present invention will be described. In this step, the above-mentioned 1-bromo-3-formyl-5-trifluoromethylbenzene is converted into the following general formula [4].
H ₂ NOR [4]
And 3-hydroxy-5-trifluoromethylbenzaldoxime to give 3-bromo-5-trifluoromethylbenzaldoxime. The hydroxyamines represented by the general formula [4] are hydroxylamines in which R is a hydrogen atom, an alkyl group or an aralkyl group, specifically, hydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine, O -Propylhydroxylamine, O-isopropylhydroxylamine, On-butylhydroxylamines, O-isobutylhydroxylamine, O-amylhydroxylamine, O-hexylhydroxylamine, O-heptylhydroxylamine, O-octylhydroxylamine, C1-C10 alkyl hydroxylamine such as O-2-ethylhexylhydroxylamine, O-nonylhydroxylamine, O-decylhydroxylamine, O-benzylhydroxylamine, O-methylben Le hydroxylamine, aralkyl hydroxylamine such as O- phenethyl hydroxylamine is exemplified.

  In the method of the present invention, for example, adducts with hydrochloric acid, sulfuric acid, carboxylic acid and the like may be used as hydroxylamines. In the case of using an acid adduct of hydroxylamines, the resulting hydroxylamines may be used in the reaction after neutralization with a base in advance, or an acid adduct of hydroxylamines and 1-bromo-3-formyl It can also be reacted with 1-bromo-3-formyl-5-trifluoromethylbenzene simultaneously with the reaction of -5-trifluoromethylbenzene in the presence of a base to generate hydroxylamines. .

  As the base, those not involved in the reaction are used, but preferably an organic base such as pyridine, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium carbonate, water Inorganic bases such as lithium oxide, sodium hydroxide and potassium hydroxide are exemplified, and the amount used is usually 1 mol times or more, preferably 1 to 10 mol times the hydroxylamine salt.

  In the method of the present invention, any solvent that does not participate in the reaction can be used as the solvent used in the reaction in the third step. For example, water, ether, alcohol, amide, nitrile, aliphatic hydrocarbon can be used. , Aromatic hydrocarbon-based, amine-based and halogenated hydrocarbon-based solvents can be used. Typical examples of these solvents include tetrahydrofuran, diethyl ether, methanol, ethanol, dimethylformamide, acetonitrile, hexane, benzene, toluene, pyridine, triethylamine, chloroform, methylene chloride, chlorobenzene and the like. Species or a combination of two or more can be used.

  The reaction temperature is usually -20 to 150 ° C and is not particularly limited, but is preferably 10 ° C to 40 ° C, and around 25 ° C is a temperature at which the reaction proceeds smoothly.

  3-Bromo-5-trifluoromethylbenzaldoxime can be obtained almost quantitatively from the reaction mixture obtained in the reaction of the third step by operations such as extraction, liquid separation, concentration, distillation, crystallization and the like. In some cases, 3-bromo-5-trifluoromethylbenzaldoxime may proceed to the next step as it is without being isolated. In addition, the oximes obtained have two types of isomers, a syn isomer and an anti isomer. In the fourth step of the present invention, both isomers obtain a single product after the reaction. The oximes used in the process can be used as single isomers or as a mixture of both isomers.

  Next, the fourth step of the present invention will be described. This step is a step in which 3-bromo-5-trifluoromethylbenzaldoxime is dehydrated to give 3-bromo-5-trifluoromethylbenzonitrile. In this step, following the third step, a dehydrating agent may be allowed to act on the reaction mixture, and the oxime obtained in the previous step is not necessarily isolated.

  As the dehydrating agent used in this step, known substances used for dehydration of aldoxime, such as formic acid, acetic anhydride, thionyl chloride, phosphorus (V) oxide, dicyclohexylcarbodiimide, cyanuric chloride, titanium (IV) chloride or benzenesulfonyl And chloride. The reaction temperature is about 0 ° C to 300 ° C, preferably about 10 ° C to 250 ° C, particularly preferably 20 ° C to 150 ° C. If it is less than 20 ° C., the reaction is slow. On the other hand, when the temperature exceeds 150 ° C., by-products are likely to be generated, and excessive heating is inferior in energy efficiency and is not preferable from the viewpoint of economy. Further, since the pressure does not affect the reaction, it is generally carried out at atmospheric pressure. However, it can also be carried out at 0.0001 to 1.0 MPa, preferably 0.001 to 0.5 MPa, particularly 0.01 to 0.2 MPa. The amount of dehydrating agent is not particularly limited, but generally at least 1 mole of dehydrating agent is used per mole of aldoxime. The dehydrating agent can be used in a large excess. For example, when formic acid, acetic anhydride, or the like is used, it acts as a diluent (solvent), and the reaction proceeds particularly smoothly. After completion of the reaction, 3-bromo-5-trifluoromethylbenzonitrile can be obtained by ordinary means such as filtration, extraction, distillation, recrystallization and the like. If necessary, it can also be purified by distillation, column chromatography, recrystallization or the like.

  Next, the fifth step of the present invention will be described. In this step, the above-mentioned 3-bromo-5-trifluoromethylbenzonitrile is reacted with an alkyl magnesium halide, magnesium metal, or alkyl lithium to produce 3-trifluoromethyl-5-cyanophenyl magnesium halide or 3-trifluoromethyl. This is a step of converting to -5-cyanophenyllithium and then formylating to give 3-formyl-5-trifluoromethylbenzonitrile.

  Examples of the conversion method to 3-trifluoromethyl-5-cyanophenyl magnesium halide used in this step include a method using an alkyl magnesium halide and a method using magnesium metal.

First, a method using an alkyl magnesium halide will be described. The alkylmagnesium halide used in this method has the general formula [5]
R'MgZ [5]
(In the formula, R ′ represents an alkyl group, and Z represents a halogen (chlorine, bromine, or iodine)). The alkyl group represented by R ′ may be linear or branched, and examples thereof include an alkyl group having 1 to 8 carbon atoms, and specifically include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. , Isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group and the like. The halogen atom represented by Z is preferably a chlorine atom or a bromine atom.

  In this method, first, 3-bromo-5-trifluoromethylbenzonitrile and alkylmagnesium halide are reacted in a suitable solvent, preferably in an inert gas atmosphere, to give 3-trifluoromethyl-5-cyanophenyl. Get magnesium halide.

  The amount of 3-bromo-5-trifluoromethylbenzonitrile and alkylmagnesium halide used is usually 0.8 to 1.5 times equivalent of alkylmagnesium halide to 3-bromo-5-trifluoromethylbenzonitrile, preferably Is 1 to 1.2 times equivalent.

  The solvent is preferably an ether solvent, and examples thereof include ethers such as diethyl ether, diisopropyl ether, t-butoxymethane, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane. The usage-amount of a solvent is suitably selected from the range of 0.5-10 times volume normally with respect to 3-bromo-5-trifluoromethylbenzonitrile, Preferably it is 1-5 times volume. As the inert gas, nitrogen gas, argon gas or the like is preferable.

  The reaction temperature at the time of reacting 3-bromo-5-trifluoromethylbenzonitrile and alkylmagnesium halide is preferably about 0 ° C. to the reflux temperature of the solvent used, preferably 0 ° C. to 65 ° C., more preferably 10 ° C. It is suitably selected from a range of ˜40 ° C. The reaction time is preferably 1 to 48 hours. In addition, the said alkyl magnesium halide may use a commercial item, and may use what was manufactured suitably.

  Next, a method using magnesium metal will be described. In this method, first, 3-bromo-5-trifluoromethylbenzonitrile and magnesium metal are reacted in a suitable solvent, preferably in an inert gas atmosphere, to give 3-trifluoromethyl-5-cyanophenylmagnesium. Get a halide.

  Magnesium metal used in this method may have any shape such as lump shape, tape shape, foil shape, flake shape, shaving shape, powder shape, but from the point of reactivity, flake shape, shaving shape, powder shape. Is preferable, and powder is particularly preferable. The amount of magnesium metal used is usually 0.8 to 5 times equivalent, preferably 1 to 2 times equivalent to 3-bromo-5-trifluoromethylbenzonitrile.

  The solvent is preferably an ether solvent, and examples thereof include ethers such as diethyl ether, diisopropyl ether, t-butoxymethane, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane. The usage-amount of a solvent is suitably selected from the range of 0.5-10 times volume normally with respect to 3-bromo-5-trifluoromethylbenzonitrile, Preferably it is 1-5 times volume. As the inert gas, nitrogen gas, argon gas or the like is preferable.

  The reaction temperature at the time of reacting 3-bromo-5-trifluoromethylbenzonitrile and alkylmagnesium halide is from 0 ° C. to the reflux temperature of the solvent used, preferably 0 ° C. to 100 ° C., more preferably 10 ° C. It is suitably selected from the range of ˜80 ° C. The reaction time is preferably 1 to 48 hours.

  Examples of the method for conversion to 3-trifluoromethyl-5-cyanophenyllithium used in this step include a method using alkyllithium.

The alkyl lithium used in this method is represented by the general formula [6].
TLi [6]
(Wherein T represents an alkyl group)
It is represented by The alkyl group represented by T may be linear or branched, and examples thereof include an alkyl group having 1 to 8 carbon atoms. Specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Examples include isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group and the like.

  In this method, first, 3-bromo-5-trifluoromethylbenzonitrile and alkyllithium are reacted in a suitable solvent, preferably in an inert gas atmosphere, to give 3-trifluoromethyl-5-cyanophenyllithium. Get.

  The amount of 3-bromo-5-trifluoromethylbenzonitrile and alkyllithium used is usually 0.8 to 1.5 times equivalent of alkylmagnesium halide to 3-bromo-5-trifluoromethylbenzonitrile, preferably It is 1-1.2 times equivalent.

  Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, butyl methyl ether, diisopropyl ether, and ethylene glycol dimethyl ether, alkanes such as n-pentane, n-hexane, n-heptane, and n-octane, benzene, and toluene. An aromatic compound such as xylene can be exemplified, but is not limited thereto. These solvents may be used alone or in combination of two or more. The usage-amount of a solvent is suitably selected from the range of 0.5-10 times volume normally with respect to 3-bromo-5-trifluoromethylbenzonitrile, Preferably it is 1-5 times volume. As the inert gas, nitrogen gas, argon gas or the like is preferable.

  The reaction temperature at the time of reacting 3-bromo-5-trifluoromethylbenzonitrile and alkyllithium is from −150 ° C. to 200 ° C., preferably from −110 ° C. to the reflux temperature of the solvent used. The reaction time is preferably 1 to 48 hours. In addition, the said alkyl lithium may use the commercial item diluted with the solvent, and may use what was manufactured suitably.

  In this step, when 3-trifluoromethyl-5-cyanophenylmagnesium halide or 3-trifluoromethyl-5-cyanophenyllithium obtained by the above-described method is left in the reaction system for a long time, the compound itself decomposes. As a result, the yield of 3-formyl-5-trifluoromethylbenzonitrile, which is the product, does not proceed well and the yield of 3-formyl-5-trifluoromethylbenzonitrile is reduced. Alternatively, it is preferable to synthesize 3-trifluoromethyl-5-cyanophenyllithium and subsequently formylate it.

  As the formylating agent to be used, those of various known structures such as N, N-dimethylformamide (DMF), N-formylpiperidine, N-formylmorpholine, N-methylformanilide can be used. N-formylpiperidine and N-formylmorpholine are preferable from the viewpoint of reactivity, and DMF is preferable from the economical viewpoint.

  The amount of the formylating agent used is usually 0.8 to 1.5 times equivalent, preferably 1 to 3-trifluoromethyl-5-cyanophenylmagnesium halide or 3-trifluoromethyl-5-cyanophenyllithium. -1.2 times equivalent. In this reaction, a formylating agent is added to 3-trifluoromethyl-5-cyanophenyl magnesium halide or 3-trifluoromethyl-5-cyanophenyl lithium (usually dissolved in a solvent) obtained in advance. It is carried out by adding.

  The above reaction is performed in air, but is preferably performed in an inert gas such as nitrogen or argon. In this step, the reaction temperature is usually −100 to 100 ° C., preferably −78 to 80 ° C., more preferably −20 to room temperature.

  After the reaction is completed, 3-formyl-5-trifluoromethylbenzonitrile can be obtained by usual means such as filtration, extraction, distillation, recrystallization and the like. If necessary, it can be purified by distillation, column chromatography, recrystallization or the like.

  Next, the sixth step of the present invention will be described. This step is a step of reducing 3-formyl-5-trifluoromethylbenzonitrile as described above using a reducing agent to obtain 3-hydroxymethyl-5-trifluoromethylbenzonitrile.

  Examples of the reduction method used in this step include a reduction method using various hydrides and a catalytic hydrogen reduction method using hydrogen gas and various metal catalysts.

In the case of reduction using hydrides, hydrides used include sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ), lithium aluminum hydride (LiAlH ₄ ), zinc borohydride (Zn). (BH _{4) 2),} lithium tri -t- butoxy alumino hydride _{(LiAlH (Ot-C 4 H} 9) 3), lithium trimethoxy aluminosilicate hydride _{(LiAlH (OCH 3) 3)} , diisobutylaluminum hydride ((i-C ₄ H ₉ ) ₂ AlH), sodium bis (methoxyethoxy) aluminum hydride (NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ ), borane-tetrahydrofuran complex (BH ₃ · THF) and the like can be used. Among these, from the viewpoints of economy, ease of handling, availability, etc., sodium borohydride (NaBH ₄ ), lithium aluminum hydride (LiAlH ₄ ), lithium tri-t-butoxyaluminohydride (LiAlH ( _{Ot-C 4 H 9) 3} ), diisobutylaluminum hydride _{((i-C 4 H 9} ) 2 AlH), sodium hydride bis (methoxyethoxy) aluminum _{(NaAlH 2 (OCH 2 CH 2} OCH 3) 2) are preferred .

The amount of the reducing agent used is preferably at least the number of moles represented by the following [Formula 1] with respect to 1 mole of 3-formyl-5-trifluoromethylbenzonitrile.

Required number of moles of reducing agent = 2 / number of active hydrogens contained in the reducing agent molecule [Formula 1]

That is, in the case of sodium borohydride (NaBH ₄ ) or lithium aluminum hydride (LiAlH ₄ ), it is 0.5 mol or more, and lithium tri-t-butoxyaluminohydride (LiAlH (Ot—C ₄ H ₉ ) ₃ ), Diisobutylaluminum hydride ((i-C ₄ H ₉ ) ₂ AlH), and in the case of sodium bis (methoxyethoxy) aluminum hydride, it is 1.0 mol or more. . These reducing agents are usually used 0.8 to 5 times the required number of moles, but preferably 1 to 3 times. Of course, further use is possible, but depending on conditions, overreduction, that is, reduction of formyl group to methyl group may occur, which is not preferable.

  In this step, a solvent may be used. Examples of the solvent include water, DMF, dimethyl sulfoxide (DMSO), alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, butyl methyl ether and diisopropyl ether, n-pentane, Examples include, but are not limited to, alkanes such as n-hexane, n-heptane, and n-octane, and aromatic compounds such as benzene, toluene, and xylene. These solvents may be used alone or in combination of two or more.

 The above reaction is carried out in air, but is preferably carried out in an inert gas such as nitrogen or argon. In this step, the reaction temperature is usually −100 to 100 ° C., preferably −78 to 50 ° C.

  In the case of using catalytic hydrogen reduction, a known catalyst can be used regardless of whether the reaction system is a heterogeneous system or a homogeneous system. preferable. Accordingly, metals or metal oxides such as palladium, ruthenium, rhodium, platinum oxide, copper and chromium, or those in which these are supported on a support such as activated carbon, alumina or diatomaceous earth are usually used. For example, activated carbon with palladium, activated carbon with palladium hydroxide, barium sulfate with palladium, calcium carbonate with palladium, strontium carbonate with palladium, palladium black, silica gel with palladium, platinum dioxide, activated carbon with platinum, platinum black, Raney nickel, activated carbon with ruthenium, Known materials such as activated carbon with rhodium and copper chromite can be used. The amount used varies depending on the catalyst used, but is usually 0.0001 to 1 mol%, preferably 0.001 to 0.1 mol%, based on 3-formyl-5-trifluoromethylbenzonitrile.

 When using catalytic hydrogen reduction, an inert solvent may be used as a solvent. Examples of such solvents include alcohols, ethers, carboxylic acids, esters, amides, water, and the like, and examples include methanol, ethanol, tetrahydrofuran, diethyl ether, acetic acid, ethyl acetate, dimethylformamide, and the like. Not limited. These solvents may be used alone or in combination of two or more.

 The pressure of hydrogen varies depending on the conditions of the solvent, catalyst, etc., and can be employed from normal pressure to about 100 atm. Preferably, 1 atm or more is used. The reaction temperature is usually in the range of −10 ° C. to 150 ° C.

  After completion of the reaction, 3-hydroxymethyl-5-trifluoromethylbenzonitrile can be obtained by ordinary means such as extraction, distillation, recrystallization and the like. If necessary, it can be purified by column chromatography or recrystallization.

  Next, the seventh step of the present invention will be described. This step is a step of brominating the above-mentioned 3-hydroxymethyl-5-trifluoromethylbenzonitrile with a brominating agent to obtain 3-bromomethyl-5-trifluoromethylbenzonitrile.

Examples of the brominating agent used in this step include bromine (Br ₂ ), hydrogen bromide, titanium tetrabromide, zinc bromide, phosphorus tribromide, phosphorus pentabromide, N-bromosuccinimide (NBS), tetra Known materials such as carbon bromide, N-bromoacetamide (NBA), thionyl bromide, trimethylsilyl bromide can be used. Of these, bromine (Br ₂ ), hydrogen bromide, and N-bromosuccinimide (NBS) are preferable from the viewpoints of economy and availability, and hydrogen bromide that does not require additional additives is particularly preferable.

  When hydrogen bromide is used, gas may be used, or one dissolved in water or various solvents may be used, but one dissolved in water from the viewpoint of ease of handling and economy, That is, it is preferable to use hydrobromic acid. Although there is no special restriction | limiting in the density | concentration of hydrobromic acid, 10 to 50% is preferable and 45 to 50% is especially preferable from availability.

  The amount of hydrobromic acid used is 1 mol or more per 1 mol of 3-hydroxymethyl-5-trifluoromethylbenzonitrile in terms of dissolved hydrogen bromide, but 1-10 mol. , Preferably 1 to 8 mol, more preferably 1 to 5 mol. An amount of 1 mol or less is not preferable because the conversion rate of 3-hydroxymethyl-5-trifluoromethylbenzonitrile is lowered. Moreover, although 10 mol or more can also be used, since it will hydrolyze a cyano group and a selectivity may fall when it uses it in large quantities, it is unpreferable.

  In this step, a solvent may be used. Examples of such a solvent include alcohols, ethers, carboxylic acids, esters, amides, water and the like. Typical examples of these include, but are not limited to, methanol, ethanol, tetrahydrofuran (THF), diethyl ether, acetic acid, ethyl acetate, N, N-dimethylformamide (DMF), and the like. These solvents may be used alone or in combination of two or more.

  This step is performed at about 25 to 150 ° C, preferably 50 to 120 ° C, and more preferably 70 to 110 ° C. A temperature higher than 150 ° C. is not preferable because hydrolysis of the cyano group occurs and the selectivity may decrease.

  After completion of the reaction, 3-bromomethyl-5-trifluoromethylbenzonitrile can be obtained by ordinary means such as extraction, distillation, recrystallization and the like. If necessary, it can be purified by column chromatography or recrystallization.

  There is no particular limitation on the reaction time required for each step described above, but the optimum reaction time varies depending on the temperature, the amount of catalyst used, and the like. In any step, it is preferable to carry out the reaction while measuring the progress of the reaction by a general-purpose analysis means such as gas chromatography and confirm that the raw materials are sufficiently consumed, and then terminate the reaction step. .

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these embodiments.
[First Step] Production of 1-bromo-3-dichloromethylbenzotrifluoride In a 100 mL stainless steel pressure-resistant reaction vessel equipped with a stirrer and a thermometer protective tube, 60.0 g of 1,3-dichloromethylbenzotrifluoride (0.262 mol) , Purity 92%), bromine 23.0 g (0.144 mol, 0.55 equivalent), anhydrous ferric chloride 4.25 g (0.0262 mol, 0.1 equivalent), and 5.0 g chlorine (0 .14 mol, 0.52 equivalents). It heated in the oil bath and heated up until the internal temperature became 50 degreeC. After 2 hours, 5.2 g (0.14 mol, 0.54 equivalent) of chlorine was added to make a total of 10.2 g (0.28 mol, 1.06 equivalent). Hydrogen chloride generated in the reaction system was sequentially purged to maintain the reaction pressure at 0.5 to 0.8 MPa. The reaction was terminated when the reaction was carried out for 7 hours while maintaining the reaction temperature at 45 to 55 ° C.

 After completion of the reaction, the reactor was cooled, and the contents were taken out and washed with an aqueous sodium sulfite solution (60 ml) to recover 68 g of organic matter. This organic substance was distilled to obtain 58 g (yield 72%, purity 86%) of the target 1-bromo-3-dichloromethylbenzotrifluoride (boiling point 74 ° C./270 Pa).

[Second Step] Production of 1-bromo-3-formyl-5-trifluoromethylbenzene 1-Bromo-3-dichloromethylbenzotrifluoride 46. In a 100 ml three-necked flask equipped with a thermometer, a dropping funnel and a reflux condenser. 1 g (0.150 mol) and 486 mg (0.003 mol, 0.02 equivalent) of anhydrous ferric chloride were charged, and the temperature was raised to 100 ° C. with stirring. While maintaining the reaction temperature at 100 ° C. or higher, 2.97 g (0.165 mol, 1.1 equivalents) of water was added dropwise over 1 hour and a half. After completion of dropping, the mixture was further stirred for 30 minutes, and 40 ml of water was added. The aqueous layer separated into two layers was separated and extracted with 20 ml of diisopropyl ether. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated to give 39.2 g of crude 1-bromo-3-formyl-5-trifluoromethylbenzene (purity 86%). This was purified by distillation to obtain 33 g (yield 88%, purity 89%) of the target 1-bromo-3-formyl-5-trifluoromethylbenzene.

[Step 3] Production of 3-bromo-5-trifluoromethylbenzaldoxime In a 200 ml three-necked flask equipped with a thermometer, methanol (20 g), water (5 g) and hydroxylamine hydrochloride 4.23 g (60.9 mmol, 1 .1 equivalent) was added and cooled using an ice bath with stirring. To this was added 25% by weight aqueous sodium hydroxide solution (20 g), followed by 14.0 g (55.3 mmol) of 1-bromo-3-formyl-5-trifluoromethylbenzene. The ice bath was removed and the reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. After the reaction solution was washed with n-heptane (40 ml), the aqueous layer separated into two layers was separated, and concentrated hydrochloric acid (8 ml) was added to make it acidic. This aqueous layer was extracted with toluene (30 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to give 14.8 g (yield 100%, purity 76%) of the desired crude 3-bromo-5-trifluoromethylbenzaldoxime. Obtained.

[Step 4] Production of 3-bromo-5-trifluoromethylbenzonitrile In a 200 ml three-necked flask equipped with a thermometer and a reflux condenser, 14.8 g of a crude product of 3-bromo-5-trifluoromethylbenzaldoxime ( 55.3 mmol), toluene (50 ml) and thionyl chloride 13.2 g (111 mol, 2 equivalents) were added, and the temperature was raised to 60 ° C. with stirring. After stirring at 60 ° C. for 1 hour, toluene and remaining thionyl chloride were distilled off to obtain 15.4 g of crude 3-bromo-5-trifluoromethylbenzonitrile. This was distilled to obtain 12.2 g (yield 88%, purity 76%) of the desired 3-bromo-5-trifluoromethylbenzonitrile.

[Step 5] Production of 3-formyl-5-trifluoromethylbenzonitrile In a 200 ml three-necked flask equipped with a thermometer, 4.1 g (16.4 mmol) of 3-bromo-5-trifluoromethylbenzonitrile, THF (20 ml) ) Was added, and the mixture was cooled with stirring until the internal temperature reached -18 ° C. Then, 8.2 ml (16.4 mmol, 1 equivalent) of a 2 mol / l tetrahydrofuran solution of isopropylmagnesium chloride was added dropwise over 15 minutes. The internal temperature rose to -12 ° C. The mixture was stirred for 1 hour while maintaining this temperature. Thereafter, 1.89 g (16.4 mmol, 1 equivalent) of N-formylmorpholine was added dropwise, and the reaction solution was warmed to room temperature and stirred at room temperature for 1 hour. 2 mol / l hydrochloric acid aqueous solution (30 ml) was added after completion | finish of reaction, and it stirred at room temperature for 1 hour. The aqueous layer separated into two layers was separated and extracted with 10 ml of diisopropyl ether. The organic layers were combined, washed with 10 ml of saturated aqueous sodium hydrogen carbonate solution and 10 ml of saturated brine, dried over magnesium sulfate, filtered and evaporated to give the desired crude 3-formyl-5-trifluoromethylbenzonitrile. 3.67g of was obtained. By adding 5 ml of diisopropyl ether and 4 ml of n-heptane to this crude 3-formyl-5-trifluoromethylbenzonitrile, completely dissolving it, cooling to 5 ° C., recrystallizing overnight, filtering and drying, 1.63 g (yield 50%, purity 94.6%) of the desired 3-formyl-5-trifluoromethylbenzonitrile was obtained.

[Example 2] Production of 3-hydroxymethyl-5-trifluoromethylbenzonitrile In a 50 ml three-necked flask equipped with a thermometer, 3.90 g (19.6 mmol) of 3-formyl-5-trifluoromethylbenzonitrile, THF ( 20 ml) was added, and the mixture was cooled with stirring until the internal temperature reached 5 ° C. Then 0.741 g (19.6 mmol, 1.0 equiv) of sodium borohydride was added. Thereafter, the mixture was stirred at room temperature for 2 hours. After adding 20 ml of 2M hydrochloric acid to the reaction solution, the mixture was stirred for 30 minutes. The aqueous layer separated into two layers was separated and extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of saturated brine, dried over magnesium sulfate, filtered and evaporated to give 3.91 g of the desired 3-hydroxymethyl-5-trifluoromethylbenzonitrile (yield). 99%, purity 98.7%).

[Example 3] Production of 3-bromomethyl-5-trifluoromethylbenzonitrile In a 50 ml three-necked flask equipped with a thermometer and a reflux condenser, 3.91 g (19.4 mmol) of 3-hydroxymethyl-5-trifluoromethylbenzonitrile was prepared. ), 47% hydrobromic acid (10.9 g, 63.4 mmol, 4 equivalents) was added, and the mixture was heated to 90 ° C. with stirring. While maintaining the reaction temperature at 90 ° C. or higher, the mixture was stirred for 9 hours and then cooled. Subsequently, water (20 ml) was added and the mixture was stirred and separated into two layers. The aqueous layer was extracted with 20 ml of diisopropyl ether. The organic layers were combined and washed with 20 ml of saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 4.40 g of crude 1-bromo-3-formyl-5-trifluoromethylbenzene (yield 86%, purity 91%). This crude 1-bromo-3-formyl-5-trifluoromethylbenzene was subjected to silica gel column chromatography, and 4.0 g of 1-bromo-3-formyl-5-trifluoromethylbenzene (yield 78%, purity). 99%).

Claims (9)

A process for producing 3-formyl-5-trifluoromethylbenzonitrile, comprising the following five steps.
First step: 3-dihalogenomethylbenzotrifluoride represented by the general formula [1]

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene represented by the general formula [2]

(Wherein XY represents the same or different halogen (fluorine, chlorine, bromine, or iodine))
Obtaining.
Second step: a step of hydrolyzing the 1-bromo-3-dihalogenomethyl-5-trifluoromethylbenzene to obtain 1-bromo-3-formyl-5-trifluoromethylbenzene.
Third step: A step of reacting the 1-bromo-3-formyl-5-trifluoromethylbenzene with hydroxylamines or an acid adduct thereof to obtain 3-bromo-5-trifluoromethylbenzaldoxime.
Fourth step: a step of dehydrating the 3-bromo-5-trifluoromethylbenzaldoxime to obtain 3-bromo-5-trifluoromethylbenzonitrile.
Fifth step: 3-bromo-5-trifluoromethylbenzonitrile is reacted with alkylmagnesium halide, magnesium metal, or alkyllithium to produce 3-trifluoromethyl-5-cyanophenylmagnesium halide or 3-trifluoromethyl. A step of converting to 5-cyanophenyllithium and then formylating to give 3-formyl-5-trifluoromethylbenzonitrile. The 3-formyl-5-trifluoromethylbenzonitrile obtained by the method of claim 1 is further reduced (sixth step) to produce 3-hydroxymethyl-5-trifluoromethylbenzonitrile Method. The 3-hydroxymethyl-5-trifluoromethylbenzonitrile obtained by the method of claim 2 is further brominated (seventh step), and 3-bromomethyl-5-trifluoromethylbenzonitrile is obtained. Production method. 4. The bromination agent according to any one of claims 1 to 3, wherein the brominating agent used when brominating 3-dihalogenomethylbenzotrifluoride (first step) is bromine (Br ₂ ). The method according to any one of claims 1 to 3. 5. The method according to claim 4, wherein, when 3-dihalogenomethylbenzotrifluoride is brominated with bromine (Br ₂ ) (first step), chlorine (Cl ₂ ) coexists and a Lewis acid catalyst coexists. The method of claim 4. In Claim 4, when brominating 3-dihalogenomethylbenzotrifluoride with bromine (Br ₂ ) (first step), chlorine (Cl ₂ ) coexists and a catalyst containing iron (Fe) coexists. The method according to claim 4, wherein: In Claim 4, when brominating 3-dihalogenomethylbenzotrifluoride with bromine (Br ₂ ) (first step), chlorine (Cl ₂ ) is allowed to coexist and a catalyst containing iron (Fe) is allowed to coexist. The method according to claim 4, wherein the reaction is performed at 25 to 100 ° C. The hydrobromic acid is used as a brominating agent in bromination of 3-hydroxymethyl-5-trifluoromethylbenzonitrile according to claim 3 (seventh step). Of 3-bromomethyl-5-trifluoromethylbenzonitrile. In claim 3, when brominating 3-hydroxymethyl-5-trifluoromethylbenzonitrile (seventh step), hydrobromic acid is used as a brominating agent and the reaction is carried out at 25 to 150 ° C. The method for producing 3-bromomethyl-5-trifluoromethylbenzonitrile according to claim 3, wherein: